Peng Lee, M.D., Ph.D.

Bmp7 Functions via a Polarity Mechanism to Promote Cloacal Septation
Xu, Kun; Wu, Xinyu; Shapiro, Ellen; Huang, Honging; Zhang, Lixia; Hickling, Duane; Deng, Yan; Lee, Peng; Li, Juan; Lepor, Herbert; Grishina, Irina
2012 ;7(1):e29372-e29372, PLoS ONE
BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations
— id: 149933, year: 2012, vol: 7, page: e29372, stat: Journal Article,

Patch TMA Construction Using Pre-Existing Slides as Source of Tissue When Paraffin Blocks Are Unavailable
Deng, F-M; Zhao, Y.; Kong, X.; Lee, P.; Melamed, J.
2011 FEB ;91(6):449A-449A, Laboratory investigation
— id: 134487, year: 2011, vol: 91, page: 449A, stat: Journal Article,

Patch TMA Construction Using Pre-Existing Slides as Source of Tissue When Paraffin Blocks Are Unavailable
Deng, F-M; Zhao, Y.; Kong, X.; Lee, P.; Melamed, J.
2011 FEB ;24(11):449A-449A, Modern pathology
— id: 132758, year: 2011, vol: 24, page: 449A, stat: Journal Article,

microRNA Associated with Aggressive Prostate Cancer in Racial Disparity
Huang, H.; Wu, X.; Zhou, L.; Li, Y.; Basturk, O.; Ostrer, H.; Freedland, S.; Osman, I.; Reuter, V.; Melamed, J.; Lee, P.
2011 FEB ;91(6):199A-199A, Laboratory investigation
— id: 134484, year: 2011, vol: 91, page: 199A, stat: Journal Article,

microRNA Associated with Aggressive Prostate Cancer in Racial Disparity
Huang, H.; Wu, X.; Zhou, L.; Li, Y.; Basturk, O.; Ostrer, H.; Freedland, S.; Osman, I.; Reuter, V.; Melamed, J.; Lee, P.
2011 FEB ;24(11):199A-199A, Modern pathology
— id: 132755, year: 2011, vol: 24, page: 199A, stat: Journal Article,

Association of overexpression of TIF1gamma with colorectal carcinogenesis and advanced colorectal adenocarcinoma
Jain, Shilpa; Singhal, Shashideep; Francis, Franto; Hajdu, Cristina; Wang, Jin-Hua; Suriawinata, Arief; Wang, Yin-Quan; Zhang, Miao; Weinshel, Elizabeth H; Francois, Fritz; Pei, Zhi-Heng; Lee, Peng; Xu, Ru-Liang
2011 Sep 21;17(35):3994-4000, World journal of gastroenterology : WJG
AIM: To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1gamma), Smad4 and transforming growth factor-beta (TGFbetaR) across a spectrum representing colorectal cancer (CRC) development. METHODS: Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1gamma, Smad4 and TGFbetaRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). RESULTS: Overexpression of TIF1gamma was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFbetaRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1gamma overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1gamma overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). CONCLUSION: The findings suggest that over-expression of TIF1gamma occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome
— id: 140416, year: 2011, vol: 17, page: 3994, stat: Journal Article,

Impact of race on survival in patients with clinically nonmetastatic prostate cancer who deferred primary treatment
Koscuiszka M; Hatcher D; Christos PJ; Rose AE; Greenwald HS; Chiu YL; Taneja SS; Mazumdar M; Lee P; Osman I
2011 Oct 21;:?-?, Cancer
BACKGROUND: Prostate cancer (PCa) racial disparity studies typically focus on survival differences after curative treatment. The authors of this report hypothesized that comparing mortality rates between African American (AA) and Caucasian American (CA) patients who deferred primary treatment for clinically nonmetastatic PCa may provide a better assessment of the impact of race on the natural course of PCa. METHODS: The pathology database of the New York Veterans Administration Medical Center (VAMC), an equal access-of-care facility, was searched for patients with biopsy-proven PCa. Inclusion criteria included 1) no evidence of metastatic disease or death within 3 years after diagnosis, 2) no primary treatment, and 3) a minimum of 5 years of follow-up for survivors. RESULTS: In total, 518 patients met inclusion criteria between 1990 and 2005. AA patients were younger (P = .02) and had higher median prostate-specific antigen (PSA) levels (P = .001) at the time of diagnosis compared with CA patients. In a multivariate model, higher Gleason score and PSA level were associated with increased mortality (P = .001 and P = .03, respectively), but race was not a predictor of death from PCa. CONCLUSIONS: The current data suggested that race did not have a major impact on survival in patients with PCa who deferred primary treatment for clinically nonmetastatic disease. Cancer 2011. (c) 2011 American Cancer Society
— id: 139502, year: 2011, vol: , page: ?, stat: Journal Article,

Natura-Alpha Targets Forkhead Box M1 and Inhibits Androgen-Dependent and -Independent Prostate Cancer Growth and Invasion
Lee P; Li Y; Ligr M; McCarron J; Daniels G; Zhang D; Zhao X; Ye F; Wang J; Liu X; Osman I; Mencher S; Lepor H; Wang LG
2011 Jul 1;17(13):4414-4424, Clinical cancer research
PURPOSE: The development of new effective therapeutic agents with minimal side effects for prostate cancer treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine - Qing Dai (Indigo Naturalis), has been used to treat leukemia for decades. However, the anti-cancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in prostate cancer.EXPERIMENTAL DESIGN: Human prostate cancer cell lines were treated with or without Natura-alpha followed by cell growth and invasion assays measured. The anti-tumor effects of Natura-alpha were examined in nude mice tumor xenograft models, as well as in a patient with advanced hormone refractory metastatic prostate cancer. Signal network proteins targeted by Natura-alpha were analyzed using Proteomic Pathway Array Analysis (PPAA) on xenografts.RESULTS: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP), and androgen-independent (LNCaP-AI, PC-3, and DU145) prostate cancer cells with IC50 between 4 to 10 Mum, also inhibits invasion of androgen-independent prostate cancer cells. Its anti-tumor effects were further evident in vivo tumor reduction in androgen-dependent and -independent nude mice tumor xenograft models as well as reduced tumor volume in the patient with hormone refractory metastatic prostate cancer. PPAA revealed that anti-proliferative and anti-invasive activities of Natura-alpha on prostate cancer might primarily be through its down-regulation of Forkhead box M1 (FOXM1) protein. Forced over-expression of FOXM1 largely reversed the inhibition by Natura-alpha.CONCLUSIONS: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone sensitive and hormone refractory prostate cancer with minimal side effects
— id: 133174, year: 2011, vol: 17, page: 4414, stat: Journal Article,

Metastatic balloon cell malignant melanoma: a case report and literature review
Lee, Lili; Zhou, Fang; Simms, Anthony; Wieczorek, Rosemary; Fang, Yanan; Subietas-Mayol, Antonio; Wang, Beverly; Heller, Patricia; Huang, Hongying; Pei, Zhiheng; Osman, Iman; Meehan, Shane; Lee, Peng
2011 Mar;4(3):315-321, International journal of clinical & experimental pathology
A case of metastatic balloon cell malignant melanoma (BCMM) is presented. The balloon melanoma cells (BMC) were absent in the shave biopsy of the primary lesion and present as a minor component in the wide and deep excision. A subsequent right neck lymph node metastasis showed complete replacement of the lymph node by large, foamy cells. Though the tumor was amelanocytic and Fontana-Masson stain failed to reveal melanin, it stained positively for S-100, HMB-45, and Melan-A. Ultrastructurally, the foamy cells were characterized by cytoplasmic vacuolization and a lack of melanosomes. The differential diagnosis of metastatic balloon cell malignant melanoma is broad, and clinicopathologic correlation may play a critical role in achieving the correct diagnosis
— id: 133175, year: 2011, vol: 4, page: 315, stat: Journal Article,

Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer
Ligr, Martin; Patwa, Ruzeen Rohintan; Daniels, Garrett; Pan, Lorraine; Wu, Xinyu; Li, Yirong; Tian, Liantian; Wang, Zhenxing; Xu, Ruliang; Wu, Jingjing; Chen, Fan; Liu, Jinsong; Wei, Jian-Jun; Lee, Peng
2011 ;6(10):e26250-e26250, PLoS ONE
Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis
— id: 139501, year: 2011, vol: 6, page: e26250, stat: Journal Article,

Protein Signatures for Classification and Prognosis of Gastric Cancer A Signaling Pathway-Based Approach
Wang, Daguang; Ye, Fei; Sun, Yabin; Li, Wei; Liu, Hongyi; Jiang, Jing; Zhang, Yang; Liu, Chengkui; Tong, Weihua; Gao, Ling; Sun, Yezhou; Zhang, Weijia; SeeToe, Terry; Lee, Peng; Suo, Jian; Zhang, David Y.
2011 OCT ;179(4):1657-1666, American journal of pathology
Current methods have limited accuracy in predicting survival and stratifying patients with gastric cancer for appropriate treatment. We sought to identify protein signatures of gastric cancer for classification and prognostication. The Protein Pathway Array (initial study) and Western blot (confirmation) were used to assess the protein expression in a total of 199 fresh frozen gastric samples. There were 56 paired samples divided into a training set (n = 37) and a validation set (n = 19) for the identification of differentially expressed proteins between tumor and normal tissues. There were 56 tumor samples used to identify proteins correlating with tumor and nodal staging. All 93 tumor samples were used to identify candidate proteins for predicting survival. We confirmed the survival prediction of the candidate proteins by using an additional cohort of gastric cancer samples (n = 50). There were 22 proteins differentially expressed between normal and tumor tissues. Nine proteins were selected to build the predictor to classify normal and tumor samples. Ten proteins were differentially expressed among different T stages and four of these were associated with invasive behavior. An additional four proteins were associated with lymph node metastasis. Two proteins were identified as independent risk factors for overall survival. This study indicated that some dysregulated signaling proteins could be selected as useful biomarkers for tumor classification and predicting outcome in gastric cancer patients. (Am J Pathol 2011, 179:1657-1666; DOI: 10.1016/j.ajpath.2011.06.010)
— id: 149889, year: 2011, vol: 179, page: 1657, stat: Journal Article,

Regulation of HMGA1 expression by microRNA296 affects prostate cancer growth and invasion
Wei JJ; Wu X; Peng Y; Shi G; Olca B; Yang X; Daniels G; Osman I; Ouyang J; Hernando E; Pellicer A; Rhim J; Melamed J; Lee P
2011 Mar 15;17(6):1297-1305, Clinical cancer research
PURPOSE: High mobility group AT-hook 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA mediated HMGA1 regulation will provide a promising therapeutic target in treating PC. Experimental Designs: In this study, we examined the functional relation between miR-296 and HMGA1 expression in several prostate cancer cell lines and a large prostate cancer cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296. RESULTS: Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation . Repression of HMGA1 by miR-296 is direct and sequence-specific. Importantly, ectopic miR-296 expression significantly reduced prostate cancer cell proliferation and invasion, in part through the down-regulation of HMGA1. Examining prostate cancer patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage. CONCLUSIONS: Our results indicate miR-296 regulates HMGA1 expression and is associated with PC growth and invasion
— id: 115464, year: 2011, vol: 17, page: 1297, stat: Journal Article,

Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism
Wu X; Xu K; Zhang L; Deng Y; Lee P; Shapiro E; Monaco M; Makarenkova HP; Li J; Lepor H; Grishina I
2011 Aug 15;356(2):337-349, Developmental biology (Orlando)
We have shown previously that during branching morphogenesis of the mouse prostate gland, Bone morphogenetic protein 7 functions to restrict Notch1-positive progenitor cells to the tips of the prostate buds. Here, we employed prostate-specific murine bi-genic systems to investigate the effects of gain and loss of Notch function during prostate development. We show that Nkx3.1(Cre) and Probasin(Cre) alleles drive expression of Cre recombinase to the prostate epithelium and periepithelial stroma. We investigated the effects of gain of Notch function using the Rosa(NI1C) conditional allele, which carries a constitutively active intracellular domain of Notch1 receptor. We carried out the analysis of loss of Notch function in Nkx3.1(Cre/+);RBP-J(flox/flox) prostates, where RBP-J is a ubiquitous transcriptional mediator of Notch signaling. We found that gain of Notch function resulted in inhibition of the tumor suppressor PTEN, and increase in cell proliferation and progenitor cells in the basal epithelium and smooth muscle compartments. In turn, loss of Notch/RBP-J function resulted in decreased cell proliferation and loss of epithelial and smooth muscle progenitors. Gain of Notch function resulted in an early onset of benign prostate hyperplasia by three months of age. Loss of Notch function also resulted in abnormal differentiation of the prostate epithelium and stroma. In particular, loss of Notch signaling and increase in PTEN promoted a switch from myoblast to fibroblast lineage, and a loss of smooth muscle. In summary, we show that Notch signaling is necessary for terminal differentiation of the prostate epithelium and smooth muscle, and that during normal prostate development Notch/PTEN pathway functions to maintain patterned progenitors in the epithelial and smooth muscle compartments. In addition, we found that both positive and negative modulation of Notch signaling results in abnormal organization of the prostate tissue, and can contribute to prostate disease in the adult organ
— id: 134432, year: 2011, vol: 356, page: 337, stat: Journal Article,

HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes
Wu, Jingjing; Liu, Zhaojian; Shao, Changshun; Gong, Yaoqin; Hernando, Eva; Lee, Peng; Narita, Masashi; Muller, William; Liu, Jinsong; Wei, Jian-Jun
2011 Jan 15;71(2):349-359, Cancer research
The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes
— id: 133176, year: 2011, vol: 71, page: 349, stat: Journal Article,

Distinct function of androgen receptor coactivator ARA70alpha and ARA70beta in mammary gland development, and in breast cancer
Wu, Xinyu; Chen, Fei; Sahin, Aysegul; Albarracin, Constance; Pei, Zhiheng; Zou, Xuanyi; Singh, Baljit; Xu, Ruliang; Daniels, Garrett; Li, Yirong; Wei, Jianjun; Blake, Marvin; Schneider, Robert J; Cowin, Pamela; Lee, Peng
2011 Jul;128(2):391-400, Breast cancer research & treatment
Steroid receptor coactivators are important in regulating the function of the receptors in endocrine organ development and in cancers, including breast. Androgen receptor (AR) coactivator ARA70, was first identified as a gene fused to the ret oncogene and later characterized as an AR coactivator. We previously reported that the full length ARA70alpha functions as a tumor suppressor gene and that ARA70beta functions as an oncogene in prostate cancer. Here we show that both ARA70alpha and ARA70beta function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70alpha and ARA70beta serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70alpha transgenic mice and overgrowth of mammary glands in ARA70beta transgenic mice at virgin and pregnant stages. We determined that ARA70alpha inhibited cell proliferation, and that ARA70beta promotes proliferation in MCF7 breast cancer cells. These effects were observed in hormone-free media, or in media with androgen or estrogen, though to varying degrees. Additionally, we observed that ARA70beta strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70alpha expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70alpha and ARA70beta have distinct effects in mammary gland development and in the progression of breast cancer
— id: 138162, year: 2011, vol: 128, page: 391, stat: Journal Article,

LEF1 Identifies Androgen-Independent Epithelium in the Developing Prostate
Wu, Xinyu; Daniels, Garrett; Shapiro, Ellen; Xu, Kun; Huang, Hongying; Li, Yirong; Logan, Susan; Greco, M Alba; Peng, Yi; Monaco, Marie E; Melamed, Jonathan; Lepor, Herbert; Grishina, Irina; Lee, Peng
2011 Jun;25(6):1018-1026, Molecular endocrinology
Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/beta-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult
— id: 132604, year: 2011, vol: 25, page: 1018, stat: Journal Article,

Overexpression of Transcription Intermediary Factor 1 gamma(TIF1 gamma) Is an Early Event in Colorectal Carcinogenesis and Inversely Related to Smad4 Inactivation in Colorectal Carcinoma
Jain, S; Yu, M; Singhal, S; Francis, F; Hajdu, C; Suriawinata, S; Zhang, M; Aladhamy, N; Chiriboga, L; Pan, R; Lee, P; Wang, J; Xu, R
2010 FEB ;23(3):149A-149A, Modern pathology
— id: 109933, year: 2010, vol: 23, page: 149A, stat: Journal Article,

Overexpression of Transcription Intermediary Factor 1 gamma(TIF1 gamma) Is an Early Event in Colorectal Carcinogenesis and Inversely Related to Smad4 Inactivation in Colorectal Carcinoma
Jain, S; Yu, M; Singhal, S; Francis, F; Hajdu, C; Suriawinata, S; Zhang, M; Aladhamy, N; Chiriboga, L; Pan, R; Lee, P; Wang, J; Xu, R
2010 FEB ;90(11):149A-149A, Laboratory investigation
— id: 109952, year: 2010, vol: 90, page: 149A, stat: Journal Article,

Higher Expression of Serine-213 Phosphorylated Androgen Receptor Level Is Associated With Prostate Cancer Recurrence
Jain, Shilpa; Ruoff, Rachael; Ha, Susan; Melamed, Jonathan; Wang, Jinhua; Ren, Qinghu; Lee, Peng; Logan, Susan
2010 OCT ;134(4):674-674, American journal of clinical pathology
— id: 113734, year: 2010, vol: 134, page: 674, stat: Journal Article,

Molecular genetics of hepatocellular neoplasia
Jain, Shilpa; Singhal, Shashideep; Lee, Peng; Xu, Ruliang
2010 ;2(1):105-118, American Journal of Translational Research
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer deaths worldwide. Proper classification and early identification of HCC and precursor lesions is essential to the successful treatment and survival of HCC patients. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into three subgroups: those with mutant TCF1/HNF1 alpha gene, those with mutant beta-catenin, and those without mutations in either of these loci. Hepatic adenomas with alpha-catenin mutations have a significantly greater risk for malignant transformation in comparison with the other two subgroups. Telangiectatic focal nodular hyperplasia has now been reclassified as telangiectatic adenoma due to the presence of non-random methylation patterns, consistent with the monoclonal origin which is similar to hepatic adenoma and HCC. HCC precursor lesions demonstrate unique molecular alterations of HSP70, CAP2, glypican 3, and glutamine synthetase that have proven useful in the histologic diagnosis of early HCC. Though specific genetic alterations depend on HCC etiology, the main proteins affected include cell membrane receptors (in particular tyrosine kinase receptors) as well as proteins involved in cell signaling (specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways), cell cycle regulation (i.e. p53, p16/INK4, cyclin/cdk complex), invasiveness (EMT, TGF-beta) and DNA metabolism. Advances in gene expression profiling have provided new insights into the molecular genetics of HCC. HCCs can now be stratified into two clinically relevant groups: Class A, the low survival subclass (overall survival time 30.3+/- 8.02 months), shows strong expression signatures of cell proliferation and antiapoptosis genes (such as PNCA and cell cycle regulators CDK4, CCNB1, CCNA2, and CKS2) as well as genes involving ubiquitination and sumoylation; Class B, the high survival subclass (overall survival time 83.7 +/-10.3 months), does not have the above expression signature. In fact, insights into HCC-specific alterations of signal transduction pathways and protein expression patterns have led to the development of new therapeutic agents with molecular targets such as EGFR, VEGF, or other multi-kinase inhibitors. In the future, these specific molecular alterations in HCC can potentially serve as diagnostic tools, prognostic markers, and/or therapeutic targets with the potential to alter clinical outcomes
— id: 133475, year: 2010, vol: 2, page: 105, stat: Journal Article,

Molecular classification of soft tissue sarcomas and its clinical applications
Jain, Shilpa; Xu, Ruliang; Prieto, Victor G; Lee, Peng
2010 ;3(4):416-428, International journal of clinical & experimental pathology
Sarcomas are a heterogeneous group of tumors that are traditionally classified according to the morphology and type of tissue that they resemble, such as rhabdomyosarcoma, which resembles skeletal muscle. However, the cell of origin is unclear in numerous sarcomas. Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas. Molecular classification based on the genetic alteration divides sarcomas into two main categories: (i) sarcomas with specific genetic alterations; which can further be subclassified based on a) reciprocal translocations resulting in oncogenic fusion transcripts (e.g. EWSR1-FLI1 in Ewing sarcoma) and b) specific oncogenic mutations (e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specific pattern, including leiomyo-sarcoma, and pleomorphic liposarcoma. These specific genetic alterations are an important adjunct to standard morphological and immunohistochemical diagnoses, and in some cases have a prognostic value, e. g., Ewing family tumors, synovial sarcoma, and alveolar rhabdomyosarcoma. In addition, these studies may also serve as markers to detect minimal residual disease and can aid in staging or monitor the efficacy of therapy. Furthermore, sarcoma-specific fusion genes and other emerging molecular events may also represent potential targets for novel therapeutic approaches such as Gleevec for dermatofibrosarcoma protuberans. Therefore, increased understanding of the molecular biology of sarcomas is leading towards development of newer and more effective treatment regimens. The review focuses on recent advances in molecular genetic alterations having an impact on diagnostics, prognostication and clinical management of selected sarcomas
— id: 109801, year: 2010, vol: 3, page: 416, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;23(3):199A-199A, Modern pathology
— id: 109935, year: 2010, vol: 23, page: 199A, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;90(11):199A-199A, Laboratory investigation
— id: 109954, year: 2010, vol: 90, page: 199A, stat: Journal Article,

Cellular senescence in usual type uterine leiomyoma
Laser, Jordan; Lee, Peng; Wei, Jian-Jun
2010 Apr;93(6):2020-2026, Fertility & sterility
OBJECTIVE: To evaluate the role of senescence in symptomatic patients with multifibroids. DESIGN: A cohort study. SETTING: University research laboratory. PATIENT(S): Eighty-six fibroids collected from 14 patients who underwent myomectomy or hysterectomy. INTERVENTION(S): Senescence-associated beta-galactosidase (SA-beta-Gal) stain in fresh-frozen tissue; reverse-transcription polymerase chain reaction (RT-PCR); MicroRNA in situ hybridization (MISH); immunohistochemistry in formalin-fixed paraffin-embedded tissue. MAIN OUTCOME MEASURE(S): Senescence measured by percentage of SA-beta-Gal-positive cells; levels of let-7 microRNAs measured by RT-PCR and MISH; expression of p16(INK4a), Ki-67, HMGA1, and HMGA2 scaled by immunoreactivity. RESULT(S): About 58% (48 of 82) of tumors showed significant senescent change (SA-beta-Gal positive) in >10% of the tumor volume. The overall trend was a higher level of senescence in small fibroids and older-aged women. Senescent fibroids were additionally shown to have, high levels of let-7 c, d, and f-2 and a low Ki-67 index. CONCLUSION(S): Senescence is a common cellular change in a large proportion of usual type fibroids. Similarly, senescence may explain the variation in growth rates of these tumors, and may prove to be an important molecular and cellular target in prevention of fibroid growth
— id: 99129, year: 2010, vol: 93, page: 2020, stat: Journal Article,

Tumor Suppressor Function of Androgen Receptor Coactivator ARA70{alpha} in Prostate Cancer
Ligr, Martin; Li, Yirong; Zou, Xuanyi; Daniels, Garrett; Melamed, Jonathan; Peng, Yi; Wang, Wei; Wang, Jinhua; Ostrer, Harry; Pagano, Michele; Wang, Zhengxin; Garabedian, Michael J; Lee, Peng
2010 Apr;176(4):1891-1900, American journal of pathology
Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. This is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene
— id: 107298, year: 2010, vol: 176, page: 1891, stat: Journal Article,

HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma
Mahajan, Aparna; Liu, Zhaojian; Gellert, Lan; Zou, Xuanyi; Yang, Guangyu; Lee, Peng; Yang, Ximing; Wei, Jian-Jun
2010 May;23(5):673-681, Modern pathology
Ovarian carcinoma consists of a group of histologically heterogeneous diseases involving distinct tumorigenic pathways. High-grade papillary serous carcinoma of the ovary is commonly associated with p53 mutations. HMGA2, an oncofetal protein, is found to be overexpressed in ovarian cancer. To study the function of HMGA2 in ovarian cancer, it is important to know which subtypes of ovarian cancer are associated with HMGA2 overexpression. In this study, we collected six different types of ovarian cancer and examined HMGA2 expression by immunohistochemistry, along with HMGA1, p53 and Ki-67. We found that HMGA2 overexpression was significantly higher in high-grade papillary serous carcinoma (64%) and carcinosarcoma (60%) than in other types of ovarian cancers (7-23%). HMGA2 overexpression was moderately associated with dominant p53 mutations (R=0.51). In addition, the microRNA in situ analysis revealed that let-7b, the HMGA2-negative regulators, were significantly lost in high-grade serous carcinoma. Our findings suggest that HMGA2 is an important molecular change significantly related to high-grade papillary serous carcinoma and is less common in other histological types of ovarian cancer.Modern Pathology advance online publication, 12 March 2010; doi:10.1038/modpathol.2010.49
— id: 109024, year: 2010, vol: 23, page: 673, stat: Journal Article,

Expression of Long-chain Fatty Acyl-CoA Synthetase 4 in Breast and Prostate Cancers Is Associated with Sex Steroid Hormone Receptor Negativity
Monaco, Marie E; Creighton, Chad J; Lee, Peng; Zou, Xuanyi; Topham, Matthew K; Stafforini, Diana M
2010 Apr;3(2):91-98, Translational oncology
Previous studies have shown that key enzymes involved in lipid metabolic pathways are differentially expressed in normal compared with tumor tissues. However, the precise role played by dysregulated expression of lipid metabolic enzymes and altered lipid homeostasis in carcinogenesis remains to be established. Fatty acid synthase is overexpressed in a variety of cancers, including breast and prostate. The purpose of the present study was to examine the expression patterns of additional lipid metabolic enzymes in human breast and prostate cancers. This was accomplished by analysis of published expression databases, with confirmation by immunoblot assays. Our results indicate that the fatty acid-activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), is differentially expressed in human breast cancer as a function of estrogen receptor alpha (ER) status. In 10 separate studies, ACSL4 messenger RNA (mRNA) was overexpressed in ER-negative breast tumors. Of 50 breast cancer cell lines examined, 17 (89%) of 19 ER-positive lines were negative for ACSL4 mRNA expression and 20 (65%) of 31 ER-negative lines expressed ACSL4 mRNA. The inverse relationship between ER expression and ACSL4 expression was also observed for androgen receptor status in both breast and prostate cancers. Furthermore, loss of steroid hormone sensitivity, such as that observed in Raf1-transfected MCF-7 cells and LNCaP-AI cells, was associated with induction of ACSL4 expression. Ablation of ACSL4 expression inMDA-MB-231 breast cancer cells had no effect on cell proliferation; however, sensitivity to the cytotoxic effects of triacsin C was increased three-fold in the cells lacking ACSL4
— id: 109023, year: 2010, vol: 3, page: 91, stat: Journal Article,

Novel PRKAR1A gene mutations in Carney Complex
Pan, Lorraine; Peng, Lan; Jean-Gilles, J; Zhang, Ximin; Wieczorek, Rosemary; Jain, Shilpa; Levine, Vicki; Osman, Iman; Prieto, Victor G; Lee, Peng
2010 ;3(5):545-548, International journal of clinical & experimental pathology
Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis
— id: 110695, year: 2010, vol: 3, page: 545, stat: Journal Article,

Diversity of 16S rRNA genes within individual prokaryotic genomes
Pei, Anna Y; Oberdorf, William E; Nossa, Carlos W; Agarwal, Ankush; Chokshi, Pooja; Gerz, Erika A; Jin, Zhida; Lee, Peng; Yang, Liying; Poles, Michael; Brown, Stuart M; Sotero, Steven; Desantis, Todd; Brodie, Eoin; Nelson, Karen; Pei, Zhiheng
2010 Jun;76(12):3886-3897, Applied & environmental microbiology
Analysis of intragenomic variation of 16S rRNA genes is a unique approach to examining the concept of ribosomal constraints on rRNA genes; the degree of variation is an important parameter to consider for estimation of the diversity of a complex microbiome in the recently initiated Human Microbiome Project (http://nihroadmap.nih.gov/hmp). The current GenBank database has a collection of 883 prokaryotic genomes representing 568 unique species, of which 425 species contained 2 to 15 copies of 16S rRNA genes per genome (2.22 +/- 0.81). Sequence diversity among the 16S rRNA genes in a genome was found in 235 species (from 0.06% to 20.38%; 0.55% +/- 1.46%). Compared with the 16S rRNA-based threshold for operational definition of species (1 to 1.3% diversity), the diversity was borderline (between 1% and 1.3%) in 10 species and >1.3% in 14 species. The diversified 16S rRNA genes in Haloarcula marismortui (diversity, 5.63%) and Thermoanaerobacter tengcongensis (6.70%) were highly conserved at the 2 degrees structure level, while the diversified gene in B. afzelii (20.38%) appears to be a pseudogene. The diversified genes in the remaining 21 species were also conserved, except for a truncated 16S rRNA gene in 'Candidatus Protochlamydia amoebophila.' Thus, this survey of intragenomic diversity of 16S rRNA genes provides strong evidence supporting the theory of ribosomal constraint. Taxonomic classification using the 16S rRNA-based operational threshold could misclassify a number of species into more than one species, leading to an overestimation of the diversity of a complex microbiome. This phenomenon is especially seen in 7 bacterial species associated with the human microbiome or diseases
— id: 133520, year: 2010, vol: 76, page: 3886, stat: Journal Article,

Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion
Peng, Yi; Li, Yirong; Gellert, Lan Lin; Zou, Xuanyi; Wang, Jun; Singh, Baljit; Xu, Ruliang; Chiriboga, Luis; Daniels, Garrett; Pan, Ruimin; Zhang, David Y; Garabedian, Michael J; Schneider, Robert J; Wang, Zhengxin; Lee, Peng
2010 Dec;14(12):2780-2789, Journal of cellular & molecular medicine
Hormones and their receptors play an important role in the development and progression of breast carcinoma. Although the primary focus has been on oestrogen and oestrogen receptor (ER), androgen, androgen receptor (AR) and its coactivator(s) have been implicated in tumorigenesis of breast carcinoma and warrant further investigation. AR coactivator p44/Mep50 is identified as a subunit of methylosome complex and lately characterized as an AR coactivator that enhances AR mediated transcription activity in a ligand dependent manner. In prostate cancer, p44 is expressed in the nucleus of benign epithelia and translocated into the cytoplasm in cancer cells. Furthermore, nuclear expression of p44 inhibits prostate cancer growth. In this report, we examined the expression and function of p44 in breast cancer. In addition to being an AR coactivator, p44 also functions as an ER coactivator. In contrast to findings in prostate cancer, the expression of p44 shows strong cytoplasmic expression in morphologically normal terminal ductal lobular units, while nuclear p44 is observed in both ductal carcinoma in situ and invasive carcinoma. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in MCF7 breast cancer cells in the presence of oestrogen and the process is ERalpha dependent. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during tumorigenesis in breast
— id: 138376, year: 2010, vol: 14, page: 2780, stat: Journal Article,

Copy number and gene expression differences between African American and Caucasian American prostate cancer
Rose, Amy E; Satagopan, Jaya M; Oddoux, Carole; Zhou, Qin; Xu, Ruliang; Olshen, Adam B; Yu, Jessie Z; Dash, Atreya; Jean-Gilles, Jerome; Reuter, Victor; Gerald, William L; Lee, Peng; Osman, Iman
2010 ;8(1):70-70, Journal of translational medicine
ABSTRACT: BACKGROUND: The goal of our study was to investigate the molecular underpinnings associated with the relatively aggressive clinical behavior of prostate cancer (PCa) in African American (AA) compared to Caucasian American (CA) patients using a genome-wide approach. METHODS: AA and CA patients treated with radical prostatectomy (RP) were frequency matched for age at RP, Gleason grade, and tumor stage. Array-CGH (BAC SpectralChip2600) was used to identify genomic regions with significantly different DNA copy number between the groups. Gene expression profiling of the same set of tumors was also evaluated using Affymetrix HG-U133 Plus 2.0 arrays. Concordance between copy number alteration and gene expression was examined. A second aCGH analysis was performed in a larger validation cohort using an oligo-based platform (Agilent 244K). RESULTS: BAC-based array identified 27 chromosomal regions with significantly different copy number changes between the AA and CA tumors in the first cohort (Fisher's exact test, P < 0.05). Copy number alterations in these 27 regions were also significantly associated with gene expression changes. aCGH performed in a larger, independent cohort of AA and CA tumors validated 4 of the 27 (15%) most significantly altered regions from the initial analysis (3q26, 5p15-p14, 14q32, and 16p11). Functional annotation of overlapping genes within the 4 validated regions of AA/CA DNA copy number changes revealed significant enrichment of genes related to immune response. CONCLUSIONS: Our data reveal molecular alterations at the level of gene expression and DNA copy number that are specific to African American and Caucasian prostate cancer and may be related to underlying differences in immune response
— id: 111525, year: 2010, vol: 8, page: 70, stat: Journal Article,

Reply of the Authors
Wei J.-J.; Laser J.; Lee P.
2010 ;94(6):e80-e80, Fertility & sterility
— id: 114369, year: 2010, vol: 94, page: e80, stat: Journal Article,

HMGA2: A Potential Biomarker Complement to P53 for Detection of Early-stage High-grade Papillary Serous Carcinoma in Fallopian Tubes
Wei, Jian-Jun; Wu, Jingjing; Luan, Chunyan; Yeldandi, Anjana; Lee, Peng; Keh, Pacita; Liu, Jinsong
2010 Jan;34(1):18-26, American journal of surgical pathology
Before high-grade papillary serous carcinoma (HG-PSC) becomes invasive, it is believed to be a poorly defined short-lived precursor lesion. A recent characterization of serous tubal intraepithelial carcinoma (STIC) and of the p53 signature suggested that HG-PSC may follow a stepwise progression on cellular and molecular levels. High-mobility group AT-hook 2 (HMGA2), an oncofetal protein, is overexpressed in ovarian cancer. To test whether HMGA2 can be another valuable marker for STIC, we examined HMGA2 expression in 3 groups of patients: (1) 24 patients with STIC and its invasive counterpart, HG-PSC of the fallopian tubes, (2) 24 patients with HG-PSC of the ovaries but without STIC (positive control), and (3) 30 patients with cancer and normal fallopian tubes (negative control). We found that HMGA2 was overexpressed in 75% of patients with STIC, was coexpressed with p53 in more than 50% of patients, and was completely negative in the secretory cells of the 30 patients with normal fallopian tubes. Among 7 patients with cells negative for p53 staining, HMGA2 was positive in 5; among 6 patients whose tumor cells were negative for HMGA2 in STIC, 3 were positive for HMGA2 in the invasive component; about 70% of invasive HG-PSC tumor cells were immunoreactive for both HMGA2 and TP53. In invasive carcinoma, HMGA2 overexpression was correlated with p53 (r=0.45), indicating the role of HMGA2 in p53 mediated tumor progression. Our findings of immunoreactivity for HMGA2 may lead to a novel, useful biomarker to complement p53 in the detection of early-stage serous carcinoma
— id: 105215, year: 2010, vol: 34, page: 18, stat: Journal Article,

Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas
Zavadil, Jiri; Ye, Huihui; Liu, Zhaojian; Wu, JingJing; Lee, Peng; Hernando, Eva; Soteropoulos, Patricia; Toruner, Gokce A; Wei, Jian-Jun
2010 ;5(8):e12362-e12362, PLoS ONE
BACKGROUND: Human uterine leiomyomas (ULM) are characterized by dysregulation of a large number of genes and non-coding regulatory microRNAs. In order to identify microRNA::mRNA associations relevant to ULM pathogenesis, we examined global correlation patterns between the altered microRNA expression and the predicted target genes in ULMs and matched myometria. METHODOLOGY/PRINCIPAL FINDINGS: Patterns of inverse association of microRNA with mRNA expression in ULMs revealed an involvement of multiple candidate pathways, including extensive transcriptional reprogramming, cell proliferation control, MAP kinase, TGF-beta, WNT, JAK/STAT signaling, remodeling of cell adhesion, and cell-cell and cell-matrix contacts. We further examined the correlation between the expression of the selected target gene protein products and microRNAs in thirty-six paired sets of leiomyomas and matched myometria. We found that a number of dysregulated microRNAs were inversely correlated with their targets at the protein level. The comparative genomic hybridization (CGH) in eight ULM patients revealed that partially shared deletions of two distinct chromosomal regions might be responsible for loss of cancer-associated microRNA expression and could thus contribute to the ULM pathogenesis via deregulation of target mRNAs. Last, we functionally tested the repressor effects of selected cancer-related microRNAs on their predicted target genes in vitro. CONCLUSIONS/SIGNIFICANCE: We found that some but not all of the predicted and inversely correlated target genes in ULMs can be directly regulated by microRNAs in vitro. Our findings provide a broad overview of molecular events underlying the tumorigenesis of uterine ULMs and identify select genetic and regulatory events that alter microRNA expression and may play important roles in ULM pathobiology by positively regulating tumor growth while maintaining the non-invasive character of ULMs
— id: 112544, year: 2010, vol: 5, page: e12362, stat: Journal Article,

The Expression of GPR 30, a G Protein-Coupled Receptor, in Prostate Cancer
Zhang, M; Lam, HM; Yu, MQ; Wang, JH; Ouyang, B; Jain, S; Daniels, G; Reuter, V; Gopalan, A; Osman, I; Lee, P; Ho, SM
2010 FEB ;23(3):231A-231A, Modern pathology
— id: 109938, year: 2010, vol: 23, page: 231A, stat: Journal Article,

The Expression of GPR 30, a G Protein-Coupled Receptor, in Prostate Cancer
Zhang, M; Lam, HM; Yu, MQ; Wang, JH; Ouyang, B; Jain, S; Daniels, G; Reuter, V; Gopalan, A; Osman, I; Lee, P; Ho, SM
2010 FEB ;90(11):231A-231A, Laboratory investigation
— id: 109957, year: 2010, vol: 90, page: 231A, stat: Journal Article,

Check Sample Abstracts
Alter D; Grenache DG; Bosler DS; Karcher RE; Nichols J; Rajadhyaksha A; Camelo-Piragua S; Rauch C; Huddleston BJ; Frank EL; Sluss PM; Lewandrowski K; Eichhorn JH; Hall JE; Rahman SS; McPherson RA; Kiechle FL; Hammett-Stabler C; Pierce KA; Kloehn EA; Thomas PA; Walts AE; Madan R; Schlesinger K; Nawgiri R; Bhutani M; Kanber Y; Abati A; Atkins KA; Farrar R; Gopez EV; Jhala D; Griffin S; Jhala K; Jhala N; Bentz JS; Emerson L; Chadwick BE; Barroeta JE; Baloch ZW; Collins BT; Middleton OL; Davis GG; Haden-Pinneri K; Chu AY; Keylock JB; Ramoso R; Thoene CA; Stewart D; Pierce A; Barry M; Aljinovic N; Gardner DL; Barry M; Shields LB; Arnold J; Stewart D; Martin EL; Rakow RJ; Paddock C; Zaki SR; Prahlow JA; Stewart D; Shields LB; Rolf CM; Falzon AL; Hudacki R; Mazzella FM; Bethel M; Zarrin-Khameh N; Gresik MV; Gill R; Karlon W; Etzell J; Deftos M; Karlon WJ; Etzell JE; Wang E; Lu CM; Manion E; Rosenthal N; Wang E; Lu CM; Tang P; Petric M; Schade AE; Hall GS; Oethinger M; Hall G; Picton AR; Hoang L; Imperial MR; Kibsey P; Waites K; Duffy L; Hall GS; Salangsang JA; Bravo LT; Oethinger MD; Veras E; Silva E; Vicens J; Silva E; Keylock J; Hempel J; Rushing E; Posligua LE; Deavers MT; Nash JW; Basturk O; Perle MA; Greco A; Lee P; Maru D; Weydert JA; Stevens TM; Brownlee NA; Kemper AE; Williams HJ; Oliverio BJ; Al-Agha OM; Eskue KL; Newlands SD; Eltorky MA; Puri PK; Royer MC; Rush WL; Tavora F; Galvin JR; Franks TJ; Carter JE; Kahn AG; Lozada Munoz LR; Houghton D; Land KJ; Nester T; Gildea J; Lefkowitz J; Lacount RA; Thompson HW; Refaai MA; Quillen K; Lopez AO; Goldfinger D; Muram T; Thompson H
2009 Feb;131(2):286-299, American journal of clinical pathology
The following abstracts are compiled from Check Sample exercises published in 2008. These peer-reviewed case studies assist laboratory professionals with continuing medical education and are developed in the areas of clinical chemistry, cytopathology, forensic pathology, hematology, microbiology, surgical pathology, and transfusion medicine. Abstracts for all exercises published in the program will appear annually in AJCP
— id: 138396, year: 2009, vol: 131, page: 286, stat: Journal Article,

Activation of Stat3 in renal tumors
Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan
2009 ;1(3):283-290, American Journal of Translational Research
Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target
— id: 105529, year: 2009, vol: 1, page: 283, stat: Journal Article,

Molecular mechanisms involving prostate cancer racial disparity
Hatcher, David; Daniels, Garrett; Osman, Iman; Lee, Peng
2009 ;1(3):235-248, American Journal of Translational Research
African American (AA) men with prostate cancer (PCa) have worse disease, with a higher incidence, younger age and more advanced disease at diagnosis, and a worse prognosis, compared to Caucasian (CA) men. In addition to socioeconomic factors and lifestyle differences, molecular alterations contribute to this discrepancy. In this review, we summarize molecular genetics research results interrelated with the biology of PCa racial disparity. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of the genes of the enzymes involved in androgen biosynthesis and metabolism, such as SRD5A2, CYP17, and CYP3A4. The levels of expression and CAG repeat length of AR also show racial divergence and may be critical molecular alterations for racial disparity. Growth factors and their receptors, which promote cancer cell growth, are another potential cause of the disparity; both EGFR and EPHB2, two of the most studied receptors, show interethnic differences. Differences have also been found among genes regulating cell apoptosis, such as BCL2, which is increased in PCa in the AA population. Recent developments in genetics, proteomics, and genomics, among other molecular biotechnologies, will greatly aid the advancement of translational research on PCa racial disparity, hopefully culminating in the discovery of novel mechanisms of disease, in addition to prognostic markers and novel therapeutic approaches
— id: 105528, year: 2009, vol: 1, page: 235, stat: Journal Article,

Dysplastic ("in-situ") Lesions in multofocal renal oncocytomas (oncocytosis)
Huang, Jiaoti; Lee, Peng; Mikami, Yoshiki; Melamed, Jonathan
2009 ;2(6):583-587, International journal of clinical & experimental pathology
Preneoplastic lesions for renal oncocytosis have not been well defined. We have attempted to identify the putative in-situ or dysplastic change in nephrectomy specimens with oncocytosis. Cases of multiple oncocytoma previously identified in radical nephrectomy specimens (n = 5) were reviewed for early lesions of renal oncocytosis by light microscopic analysis and by immunohistochemical studies for p53, bcl2 and MIB-1. Microscopic analysis showed that the renal cortical regions in all cases contain isolated groups of tubules partially or completely replaced by oncocytic cells with morphologic features resembling tumor cells in oncocytosis. The oncocytic cells within these tubules are increased in number and are arranged either as solid groups or as single layers in cystically dilated tubules, and may assume a hobnail appearance. They can be distinguished from small foci of oncocytosis as they do not form a coalescent group but are separated in part by intervening normal-appearing tubules. Cytologically, the cells have abundant eosinophilic, granular cytoplasm with a low nuclear/cytoplasmic ratio and demonstrate distinct cell borders. A very characteristic feature of these cells is the retraction space ('windows') between the oncocytic cells. Nuclear features of these cells are not distinctive from normal tubules. Immunostaining with Bcl-2, p53 and MIB-1 antibodies also does not differentiate the putative preneoplastic lesions from normal tubules. Thus, recognition of a putative dysplastic lesion for oncocytosis is possible by routine microscopic analysis. Identification of this lesion in a biopsy or partial nephrectomy specimen should raise the possibility of the existence of renal oncocytosis (multifocality), leading to adequate clinical management
— id: 111607, year: 2009, vol: 2, page: 583, stat: Journal Article,

LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth, and invasion
Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J; Ferrari, Anna; Lee, Peng
2009 Apr 15;69(8):3332-3338, Cancer research
A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potential marker for androgen-independent disease and as a key regulator of AR expression and prostate cancer growth and invasion. LEF1 is highly expressed in androgen-independent prostate cancer, potentially serving as a marker for androgen-independent disease
— id: 99128, year: 2009, vol: 69, page: 3332, stat: Journal Article,

Detection of BRAF kinase mutations in melanoma, ovarian, and prostate carcinomas: Evidence for tumor heterogeneity in clinical samples
Litterman A.J.; Yancovitz M.; Shapiro R.; Berman R.; Pavlick A.; Daarvishian F.; Blank S.; Lee P.; Osman I.; Polsky D.
2009 ;27(15 Suppl 1):11031-11031, Journal of clinical oncology
Background: Several studies have provided evidence that solid tumors are polyclonal malignancies, an observation which may contribute to difficulties in achieving durable treatment responses. In some patients, molecularly targeted therapies may be compromised due to heterogeneity among tumor subclones. In this study we compared conventional DNA sequencing with a fluorescent-based mutant-specific PCR (MS-PCR) assay to detect the BRAF hotspot mutation V600E in a large panel of patient tumors, including paired primary and metastatic tumors from individual patients. Methods: BRAF MS-PCR and conventional sequencing were performed on DNA from 304 tumors (112 melanoma, 110 ovarian, 82 prostate) to determine the presence of the BRAFV600E hot-spot mutation. Among the melanomas were 18 matched primary and metastatic specimens, and 40 metastatic specimens from 19 patients, each of whom had 2 or more metastases. Results: DNA sequencing detected mutations in 5/110 (4.5%) ovarian tumors, 1/82 (1.2%) prostate tumors, and 36/112 (32%) melanomas. In contrast, the MS-PCR assay detected mutations in 12/110 (11%) ovarian tumors, 15/82 (18%) prostate tumors and 85/112 (76%) melanomas. The presence of contaminating normal tissue was scored for each melanoma sample, but excess normal tissue did not influence the results using either methodology. In all cases mutations detected by sequencing were also detected by MSPCR. Among 18 patients with matched primary and metastatic melanoma, 8/18 (44%) had discordant results including 2 patients with mutant primary tumors and wild-type metastases; among the 19 patients with multiple metastases 5/19 (26%) had discordant (both wild-type and mutant) tumors. Conclusions: Using a highly sensitive BRAF mutation detection method, we observed substantial evidence for heterogeneity within clinical tumor specimens. This was especially true in melanoma samples, where multiple specimens from individual patients differed with respect to the presence of the mutant BRAF allele. These results suggest that failures of molecularly targeted therapies, such as those directed against mutant BRAF, may be due in part to a lack of clonality among the tumors under treatment
— id: 111809, year: 2009, vol: 27, page: 11031, stat: Journal Article,

Pancreatic carcinoma with multilineage (acinar, neuroendocrine, and ductal) differentiation
Newman, Kia; Stahl-Herz, Jay; Kabiawu, Oluyomi; Newman, Elliot; Wieczorek, Rosemary; Wang, Beverly; Pei, Zhiheng; Bannan, Michael; Lee, Peng; Xu, Ruliang
2009 ;2(6):602-607, International journal of clinical & experimental pathology
The preponderance of pancreatic tumors is adenocarcinoma of the ductal type; carcinomas with multiple lineage differentiation are extremely rare. We report an unusual case of pancreatic carcinoma with combined acinar and neuroendocrine differentiation and minor ductal component with concurrent acinar-ductal metaplasia (ADM), an early lesion implicated in ductal carcinogenesis. The patient is a 56-year-old man with vague complaints of dull left upper quadrant pain with radiation across the mid-portion of his abdomen. A computer tomography scan revealed an irregular enlargement of the distal 3.2 cm of the pancreatic body. A distal pancreatectomy was then performed. Histologic examination revealed a pancreatic carcinoma with cellular features of eosinophilic granular cytoplasm and salt-pepper nuclei. The acinar differentiation of the carcinoma was confirmed by positivity on periodic acid-Schiff stain resistant to diastase digestion (dPAS), positivity for antitrypsin on immunohistochemistry (IHC), and presence of zymogen granules on electron microscopy (EM). The neuroendocrine differentiation was evident by positive synaptophysin and chromogranin stain on IHC and neuroendocrine granules on EM. The ductal component was only visible by PAS stain and immunostains for CEA and CK19A and accompanied by a number of the acinar-ductal metaplasia lesions adjacent to the main tumor. Thus, the histological, histochemical, immunohistochemical and electron-microscopic evidence all suggested that the pancreatic carcinoma underwent trilineage differentiation
— id: 101289, year: 2009, vol: 2, page: 602, stat: Journal Article,

Expression of insulin-like growth factors (IGFs) and IGF signaling: molecular complexity in uterine leiomyomas
Peng, Lan; Wen, Yong; Han, Yulong; Wei, Anran; Shi, Guizhi; Mizuguchi, Masashi; Lee, Peng; Hernando, Eva; Mittal, Khush; Wei, Jian-Jun
2009 Jun;91(6):2664-2675, Fertility & sterility
OBJECTIVE: To study whether dysregulation of insulin-like growth factors (IGFs) and IGF signaling are common molecular changes in symptomatic leiomyomas (fibroids) and whether IGFs are associated with large fibroids. DESIGN: Examination of IGFs and IGF pathway genes in a large cohort of fibroids at transcriptional and translational levels. Mechanisms leading to alterations of IGFs and related genes were also analyzed. SETTING: University clinical research laboratory. PATIENT(S): Hysterectomies for symptomatic fibroids were collected: 180 cases from paraffin-embedded tissues and 50 cases from fresh-frozen tissues. INTERVENTION(S): Tissue microarray and immunohistochemistry, DNA methylation analysis, reverse-transcriptase polymerase chain reaction, and Western blot. MAIN OUTCOME MEASUREMENT(S): Transcription and translation analyses of IGF-1/2, p-AKT, p-S6K, and TSC1/2 in fibroids and matched myometrium. RESULT(S): Insulin-like growth factors and downstream effectors were dysregulated in approximately one third of fibroids. All except for IGF-2 seemed to be abnormally regulated at translation levels. Up-regulation of IGF-2 messenger RNAs was contributed by all four alternating slicing promoters. There was a positive correlation of IGF-1 and p-AKT over-expression with fibroid size. Insulin-like growth factor 1 but not IGF-2 levels directly correlated with activation of p-AKT and p-S6K. CONCLUSION(S): Altered expressions of IGFs and their related downstream proteins were found in one third of fibroids. Large fibroids show high levels of IGF-1 and p-AKT activity compared with small ones
— id: 78574, year: 2009, vol: 91, page: 2664, stat: Journal Article,

Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
Segura, Miguel F; Hanniford, Douglas; Menendez, Silvia; Reavie, Linsey; Zou, Xuanyi; Alvarez-Diaz, Silvia; Zakrzewski, Jan; Blochin, Elen; Rose, Amy; Bogunovic, Dusan; Polsky, David; Wei, Jianjun; Lee, Peng; Belitskaya-Levy, Ilana; Bhardwaj, Nina; Osman, Iman; Hernando, Eva
2009 Feb 10;106(6):1814-1819, Proceedings of the National Academy of Sciences of the United States of America
The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy
— id: 92154, year: 2009, vol: 106, page: 1814, stat: Journal Article,

Let-7 repression leads to HMGA2 overexpression in uterine leiomyosarcoma
Shi, Guizhi; Perle, Mary Ann; Mittal, Khush; Chen, Hua; Zou, Xuanyi; Narita, Masashi; Hernando, Eva; Lee, Peng; Wei, Jian-Jun
2009 Sep;13(9B):3898-3905, Journal of cellular & molecular medicine
Overexpression of HMGA2 is common in uterine leiomyomas (ULM). The expression of HMGA2 in its malignant counterpart - uterine leiomyosarcomas (ULMS) remains undetermined. Recently it has been shown that repression of HMGA2 by microRNA let-7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas. To test whether HMGA2 and let-7s play a role in ULMS, we examined the levels of endogenous HMGA2 and let-7 expression and found a significant correlation between these two molecules in a case-matched cohort of human ULMS. We found that overexpression of HMGA2 and let-7-mediated HMGA2 repression is a relevant molecular alteration in ULMS. Disrupting the control of HMGA2 and let-7 pairs promotes ULMS cell growth in vitro
— id: 114731, year: 2009, vol: 13, page: 3898, stat: Journal Article,

CHARACTERIZATION AND INCIDENCE OF STROKE IN FABRY DISEA
Sims, K; Politei, J; Banikazemi, M; Lee, P
2009 JUN ;31(5):S31-S31, Clinical therapeutics
— id: 101312, year: 2009, vol: 31, page: S31, stat: Journal Article,

MDM2 Expression and Regulation in Prostate Cancer Racial Disparity
Wang, Guimin; Firoz, Elnaz F; Rose, Amy; Blochin, Elen; Christos, Paul; Pollens, Danuta; Mazumdar, Madhu; Gerald, William; Oddoux, Carole; Lee, Peng; Osman, Iman
2009 ;2(4):353-360, International journal of clinical & experimental pathology
MDM2 is a key negative regulator of tumor suppressor p53. A single nucleotide polymorphism in the MDM2 promoter, SNP309, enhances transcriptional activation of MDM2 and has been associated with early onset of several types of cancer. In this study, we attempted to determine if the MDM2 SNP309 polymorphism plays a role in the aggressive phenotype seen in African American (AA) prostate cancer by examining the association between MDM2 SNP309 and MDM2 protein levels in prostate cancer (PCa) patients of different racial backgrounds. Prospectively enrolled PCa patients (AA=51, CA=50) were evaluated for MDM2 SNP309 and MDM2 protein expression. MDM2 overexpression, defined as >10% of tumor cells in three tissue cores, was assessed using immunohistochemistry on tissue microarray. MDM2 protein expression was significantly greater in CA than AA patients (78% versus 45% respectively, p=0.0007). Germline DNA was analyzed by PCR-RFLP then confirmed by DNA sequencing. MDM2 SNP309 genotype frequencies did not differ significantly between AA and CA PCa patients (AA: TT 68.6%, TG 25.5%, GG 5.9%; CA: TT 62.0%, TG 20.0%, GG 18.0%; p=0.16), suggesting that the MDM2 SNP309 allele does not play a significant role in the observed overexpression
— id: 92155, year: 2009, vol: 2, page: 353, stat: Journal Article,

Increased expression of histone deacetylaces (HDACs) and inhibition of prostate cancer growth and invasion by HDAC inhibitor SAHA
Wang, Longgui; Zou, Xuanyi; Berger, Aaron D; Twiss, Christian; Peng, Yi; Li, Yirong; Chiu, Jason; Guo, Hongfeng; Satagopan, Jaya; Wilton, Andrew; Gerald, William; Basch, Ross; Wang, Zhengxin; Osman, Iman; Lee, Peng
2009 ;1(1):62-71, American Journal of Translational Research
Histone deacetetylases (HDACs) are a group of corepressors of transcriptional activators and their levels of expression are potentially dysregulated in prostate cancer. Certain inhibitors of histone deacetylases show anti-tumor activity in prostate cancer cell lines. Here, we systemically studied the expression of HDACs in human prostate cancer and the suppression of prostate cancer growth and invasion by HDAC inhibitor SAHA. HDAC1-5 showed increased expression using a combination of DNA microarray, in-situ hybridization, and immunohistochemistry in benign and malignant human prostate tissue as well as RT-PCR and Western blot analysis on various PCa cell lines. Importantly, HDAC inhibitor SAHA suppressed, in particular, prostate cancer cell growth and invasion determined using cell proliferation and Matrigel invasion assays. The findings of this study show that the expression of HDACs and their associated corepressors are increased in prostate cancer in humans and HDAC inhibitor SAHA could serve as a potential therapeutic agent in prostate cancer in addition to anti-androgens
— id: 115887, year: 2009, vol: 1, page: 62, stat: Journal Article,

Developing a multidisciplinary prospective melanoma biospecimen repository to advance translational research
Wich, Lindsay G; Hamilton, Heather K; Shapiro, Richard L; Pavlick, Anna; Berman, Russell S; Polsky, David; Goldberg, Judith D; Hernando, Eva; Manga, Prashiela; Krogsgaard, Michelle; Kamino, Hideko; Darvishian, Farbod; Lee, Peng; Orlow, Seth J; Ostrer, Harry; Bhardwaj, Nina; Osman, Iman
2009 ;1(1):35-43, American Journal of Translational Research
Several challenges face the development and operation of a biospecimen bank linked to clinical information, a critical component of any effective translational research program. Melanoma adds particular complexity and difficulty to such an endeavor considering the unique characteristics of this malignancy. We describe here a review of biospecimen bank and our experience in establishing a multi-disciplinary, prospective, integrated clinicopathological-biospecimen database in melanoma. The Interdisciplinary Melanoma Cooperative Group (IMCG), a prospective clinicopathological and biospecimen database, was established at the New York University (NYU) Langone Medical Center. With patients' informed consent, biospecimens from within and outside NYU, clinicopathological data, and follow-up information are collected using developed protocols. Information pertaining to biospecimens is recorded in 35 fields, and clinicopathological information is recorded in 371 fields within 5 modules in a virtual network system. Investigators conducting research utilizing the IMCG biospecimen resource are blind to clinicopathological information, and molecular data generated using biospecimens are linked independently with clinicopathological data by biostatistics investigators. This translational research enterprise acts as a valuable resource to efficiently translate laboratory discoveries to the clinic
— id: 105566, year: 2009, vol: 1, page: 35, stat: Journal Article,

Stromal anti-apoptotic androgen receptor target gene c-FLIP in prostate cancer
Ye, Huihui; Li, Yirong; Melamed, Jonathan; Pearce, Patrice; Wei, Jianjun; Chiriboga, Luis; Wang, Zhengxin; Osman, Iman; Lee, Peng
2009 Feb;181(2):872-877, Journal of urology
PURPOSE: The tumor microenvironment significantly influences prostate cancer progression. Androgen receptor exerts its effect through downstream target genes to regulate prostate cancer cell proliferation. The c-FLIP gene was recently shown to be an androgen receptor target gene. c-FLIP is an inactive homologue of caspase-8 and, thus, it inhibits the death receptor mediated apoptosis pathway. c-FLIP over expression was shown to accelerate the progression of prostate cancer cells to androgen independence. We evaluated the role of c-FLIP expression in stromal cells in prostate cancer development. MATERIALS AND METHODS: We examined c-FLIP expression in 53 androgen dependent and 21 androgen independent prostate cancer stromal cells by immunohistochemical analysis. The effects of c-FLIP over expression in stromal cells on the growth and invasion of LNCaP and PC3 prostate cancer cells were determined in indirect coculture systems. RESULTS: At the androgen dependent stage the stromal c-FLIP level was increased in prostate cancer tissue. The expression level of stromal c-FLIP was associated with tumor differentiation. However, stromal c-FLIP expression was not increased in androgen independent human prostate cancer. c-FLIP over expression in stromal cells stimulated the growth and invasion of prostate cancer, including LNCaP and PC3 cells in vitro. CONCLUSIONS: These results indicate the over expression of stromal c-FLIP and its function for promoting prostate cancer growth and invasion
— id: 92157, year: 2009, vol: 181, page: 872, stat: Journal Article,

Proteomics, Pathway Array and Signaling Network-Based Medicine in Cancer
Zhang, David Y; Ye, Fei; Gao, Ling; Liu, Xiaoliang; Zhao, Xin; Che, Yufang; Wang, Hongxia; Wang, Libo; Wu, Josephine; Song, Dong; Liu, Wei; Xu, Hong; Jiang, Bo; Zhang, Weijia; Wang, Jinhua; Lee, Peng
2009 Oct 28;4(1):20-20, Cell division
ABSTRACT: Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc.) and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine
— id: 104874, year: 2009, vol: 4, page: 20, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;89:921-921, Laboratory investigation
— id: 104576, year: 2009, vol: 89, page: 921, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;22(Suppl 1):203A-203A 921, Modern pathology
— id: 104577, year: 2009, vol: 22, page: 203A, stat: Journal Article,

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations
Cai, C Q; Peng, Y; Buckley, M T; Wei, J; Chen, F; Liebes, L; Gerald, W L; Pincus, M R; Osman, I; Lee, P
2008 May 15;27(22):3201-3210, Oncogene
While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.Oncogene advance online publication, 14 January 2008; doi:10.1038/sj.onc.1210983
— id: 76447, year: 2008, vol: 27, page: 3201, stat: Journal Article,

Home-based enzyme infusion therapy for patients with Fabry disease-the collective experience
Cousins, A; Lee, P; Rorman, DH; Raas-Rothschild, A; Banikazemi, M; Waldek, S; Thompson, L
2008 MAY ;30(5):S69-S69, Clinical therapeutics
— id: 78393, year: 2008, vol: 30, page: S69, stat: Journal Article,

Impact of Socioeconomic Factors on Prostate Cancer Outcomes in Black Patients Treated with Surgery
Dash, Atreya; Lee, Peng; Zhou, Qin; Jean-Gilles, Jerome; Taneja, Samir; Satagopan, Jaya; Reuter, Victor; Gerald, William; Eastham, James; Osman, Iman
2008 Sep;72(3):641-646, Urology
OBJECTIVES: The role of socioeconomic factors in the worse outcome of black men with prostate cancer remains unclear. To determine whether socioeconomic factors affect prostate cancer outcomes, we studied a cohort of only black patients to minimize known confounding factors. METHODS: We studied black men treated with radical prostatectomy at New York Veterans Administration Medical Center and Memorial Sloan-Kettering Cancer Center between 1990 and 2005. A centralized pathology review process determined the Gleason score of all cases. Prostate-specific antigen (PSA) recurrence at both sites was defined as PSA of 0.2 or greater with a confirmatory rise. By matching patients' home zip codes to the U.S. Census Bureau database, we obtained corresponding socioeconomic data regarding median household income (income) and percentage of population with a high school (degree). We analyzed income, education, and clinical and pathological parameters for the whole cohort. RESULTS: We studied 430 black patients. They resided in neighborhoods where median household income was $41,498.10 and mean percentage of high school graduates was 73.4%. A total of 88 patients (20.9%) had PSA recurrence. Median follow-up for survivors was 37 months. Neither income nor education evaluated as continuous or categorical variables were predictors of PSA recurrence. When evaluated as composite categorical variable, the combination of greater income and education did not predict disease-free survival. CONCLUSIONS: Data suggest that socioeconomic factors have limited impact on PSA recurrence in black men treated with radical prostatectomy. Thus, biologic factors might have a role in the poor outcomes in this population
— id: 76449, year: 2008, vol: 72, page: 641, stat: Journal Article,

MicroRNA expression in the tumor-associated stroma of prostate cancer
Gellert, LL; Basturk, O; Zon, XY; Wei, JJ; Pellicer, A; Kong, XT; Melamed, J; Lee, P
2008 OCT ;130(4):5-519, American journal of clinical pathology
— id: 98126, year: 2008, vol: 130, page: 5, stat: Journal Article,

Up-regulation of nuclear hormone receptor cofactor TBLRI expression in breast adenocarcinoma
Gellert, LL; Zhang, XM; Wei, JH; Singh, B; Wieczorek, R; Gerald, W; Xu, RL; Lee, P; Basch, R
2008 OCT ;130(4):661-661, American journal of clinical pathology
— id: 86668, year: 2008, vol: 130, page: 661, stat: Journal Article,

A systematic evaluation of histopathologic criteria for adenocarcinoma of prostate using frozen sections as compared with routine permanent sections
Kong, X; Ye, H; Cetin, N; Small, J; Lee, P; Melamed, J
2008 JAN ;21(2):163A-164A, Modern pathology
— id: 75912, year: 2008, vol: 21, page: 163A, stat: Journal Article,

A systematic evaluation of histopathologic criteria for adenocarcinoma of prostate using frozen sections as compared with routine permanent sections
Kong, X; Ye, H; Cetin, N; Small, J; Lee, P; Melamed, J
2008 JAN ;88(2):163A-164A, Laboratory investigation
— id: 75934, year: 2008, vol: 88, page: 163A, stat: Journal Article,

Stromal AR inhibition of prostate cancer growth and invasion by stromal AR and association with androgen independent disease
Li, Y; Li, CX; Melamed, J; Walden, P; Peng, Y; Lepor, H; Garabedian, MJ; Lee, P
2008 ;179(4):187-187, Journal of urology
— id: 104578, year: 2008, vol: 179, page: 187, stat: Journal Article,

Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasion
Li, Yirong; Li, Caihong X; Ye, Huihui; Chen, Fei; Melamed, Jonathan; Peng, Yi; Liu, Jinsong; Wang, Zhengxin; Tsou, Hui C; Wei, Jianjun; Walden, Paul; Garabedian, Michael J; Lee, Peng
2008 Dec;12(6B):2790-2798, Journal of cellular & molecular medicine
Androgen receptor (AR) is expressed in both stromal and epithelial cells of the prostate. The majority of studies on AR expression and function in prostate cancer is focused on malignant epithelial cells rather than stromal cells. In this study, we examined the levels of stromal AR in androgen-dependent and -independent prostate cancer and the function of stromal AR in prostate cancer growth and invasion. We showed that stromal AR levels were decreased in the areas surrounding cancerous tissue, especially in androgen-independent cancer. Using two telomerase-immortalized human stromal cell lines, one AR-positive and the other AR-negative, we demonstrated that stromal cells lacking AR stimulated cell proliferation of co-cultured prostate cancer cells in vitro and enhanced tumor growth in vivo when co-injected with PC3 epithelial cells in nude mice. In contrast, stromal cells expressing AR suppressed prostate cancer growth in vitro and in vivo. In parallel with cancer growth, in vitro invasion assays revealed that stromal cells lacking AR increased the invasion ability of PC3 cell by one order of magnitude, while stromal cells expressing AR reduced this effect. These results indicate a negative regulation of prostate cancer growth and invasion by stromal AR. This provides potentially new mechanistic insights into the failure of androgen ablation therapy, and the reactivation of stromal AR could be a novel therapeutic approach for treating hormone refractory prostate cancer
— id: 76448, year: 2008, vol: 12, page: 2790, stat: Journal Article,

Expression and function of androgen receptor co-activator p44/MEP50 in invasive ductal carcinoma of breast
Lin, L; Peng, Y; Wang, J; Wei, JJ; Chiriboga, L; Singh, B; Sun, W; Gerald, W; Lee, P
2008 JAN ;21(2):43A-43A, Modern pathology
— id: 75906, year: 2008, vol: 21, page: 43A, stat: Journal Article,

Expression and function of androgen receptor co-activator P44/MEP50 in invasive ductal carcinoma of breast
Lin, L; Peng, Y; Wang, J; Wei, JJ; Chiriboga, L; Singh, B; Sun, W; Gerald, W; Lee, P
2008 JAN ;88(2):43A-43A, Laboratory investigation
— id: 75928, year: 2008, vol: 88, page: 43A, stat: Journal Article,

Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer
Peng, Yi; Chen, Fei; Melamed, Jonathan; Chiriboga, Luis; Wei, Jianjun; Kong, Xiangtian; McLeod, Maureen; Li, Yirong; Li, Caihong X; Feng, Alice; Garabedian, Michael J; Wang, Zhengxin; Roeder, Robert G; Lee, Peng
2008 Apr 1;105(13):5236-5241, Proceedings of the National Academy of Sciences of the United States of America
Androgen receptor (AR) mediates transcriptional activation of diverse target genes through interactions with various coactivators that may alter its function and help mediate the switch between prostate cell proliferation and differentiation. We recently identified p44/MEP50 as an AR coactivator and further showed that it is expressed primarily in the nucleus and cytoplasm of benign prostate epithelial and prostate cancer cells, respectively. We also showed that haploinsufficiency in p44(+/-) mice causes prostate epithelial cell proliferation. To establish direct cause-and-effect relationships, we have used p44 fusion proteins that are selectively expressed in the nucleus or cytoplasm of prostate cancer cells (LNCaP), along with RNAi analyses, to examine effects of p44 both in vitro and in vivo (in tumor xenografts). We show that preferential expression of p44 in the nucleus inhibits proliferation of LNCaP cells in an AR-dependent manner, whereas preferential expression of p44 in the cytoplasm enhances cell proliferation. These effects appear to be mediated, at least in part, through the regulation of distinct cell-cycle regulatory genes that include p21 (up-regulated by nuclear p44) and cyclin D2 and CDK6 (up-regulated by cytoplasmic p44). Importantly, we also demonstrate that altered p44 expression is associated with androgen-independent prostate cancer. Our results indicate that nuclear p44 and cytoplasmic p44 have distinct and opposing functions in the regulation of prostate cancer cell proliferation
— id: 76450, year: 2008, vol: 105, page: 5236, stat: Journal Article,

Androgen receptor coactivator ARA70alpha and ARA70beta isoform-specific antibodies: new tools for studies of expression and immunohistochemical localization
Peng, Yi; Chiriboga, Luis; Yee, Herman; Pei, Zhiheng; Wang, Zhenxing; Lee, Peng
2008 Jan;16(1):7-12, Applied immunohistochemistry & molecular morphology
ARA70 is a coactivator of androgen receptor (AR), a ligand-dependent transcription factor that plays an important role in prostate cancer. There are 2 variants of ARA70, the full length 70 kd ARA70alpha isoform and the internally spliced 35 kd ARA70beta isoform. Recent studies have suggested different expression and roles of the 2 isoforms in several endocrine malignancies, including prostate, breast, and ovarian cancers. To study the roles of these isoforms in cancers, we produced isoform-specific polyclonal antibodies. The anti-ARA70alpha antibody was raised in rabbits against 326 amino acid peptide corresponding to the internal deletion missing from ARA70beta (ARA70id), whereas the anti-ARA70beta antibody was raised against 18 amino acid polypeptide spanning the splice junction, with Gln-Gln motif unique to ARA70beta. The antisera were affinity purified on CNBr-activated sepharose 4B, and their specificity tested against bacterially expressed, Ni-column-purified ARA70alpha, ARA70beta, and ARA70id. The anti-ARA70alpha antibody recognized ARA70alpha and ARA70id, but not ARA70beta. The anti-ARA70beta antibody was specific to ARA70beta and did not cross-react with ARA70alpha or ARA70id. We then used these antibodies to detect ARA70 isoforms in crude extracts made of prostate cancer cell lines and performed immunohistochemical localization of these proteins in prostate tissues. ARA70beta localized to the cytosol, whereas ARA70alpha was found in the nucleus, supporting the notion of their dissimilar functions
— id: 76112, year: 2008, vol: 16, page: 7, stat: Journal Article,

Antiproliferative effects by let-7 repression of high-mobility group A2 in uterine leiomyoma
Peng, Yi; Laser, Jordan; Shi, Guizhi; Mittal, Khush; Melamed, Jonathan; Lee, Peng; Wei, Jian-Jun
2008 Apr;6(4):663-673, Molecular cancer research
High-mobility group A2 (HMGA2) is commonly overexpressed in large leiomyomas. HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation. As a predicted target of Let-7 microRNAs (Let-7s), HMGA2 can be repressed by Let-7s in vitro. MicroRNA profiling analysis revealed that Let-7s were significantly dysregulated in uterine leiomyomas: high in small leiomyomas and lower in large leiomyomas. To evaluate whether Let-7 repression of HMGA2 plays a major role in leiomyomas, we analyzed the molecular relationship of HMGA2 and Let-7s, both in vitro and in vivo. We first characterized that exogenous Let-7 microRNAs could directly repress the dominant transcript of HMGA2, HMGA2a. This repression was also identified for two cryptic HMGA2 transcripts in primary leiomyoma cultures. Second, we found that the endogenous Let-7s were biologically active and played a major role in the regulation of HMGA2. Then, we illustrated that Let-7 repression of HMGA2 inhibited cellular proliferation. Finally, we examined the expression levels of Let-7c and HMGA2 in a large cohort of leiomyomas (n = 120), and we found high levels of Let-7 and low levels of HMGA2 in small leiomyomas, and low levels of Let-7 and high levels of HMGA2 in large leiomyomas. Our findings suggest that the Let-7-mediated repression of HMGA2 mechanism can be an important molecular event in leiomyoma growth. (Mol Cancer Res 2008;6(4):663-73)
— id: 78575, year: 2008, vol: 6, page: 663, stat: Journal Article,

Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70
Peng, Yi; Li, Caihong X; Chen, Fei; Wang, Zhengxin; Ligr, Martin; Melamed, Jonathan; Wei, Jianjun; Gerald, William; Pagano, Michele; Garabedian, Michael J; Lee, Peng
2008 Jan;172(1):225-235, American journal of pathology
ARA70 was first identified as a gene fused to the ret oncogene in thyroid carcinoma and subsequently as a co-activator for androgen receptor (AR). Two isoforms of ARA70 have been identified: a 70-kDa version called ARA70 alpha and an internally spliced 35-kDa variant termed ARA70 beta. We have previously reported that ARA70 alpha expression is reduced in prostate cancer, and its overexpression inhibits proliferation of LNCaP prostate cancer cells. However, the function of the ARA70 beta isoform in prostate cancer is not understood. In this report we examined the effects of ARA70 beta on AR transcriptional regulation as well as prostate cancer cellular proliferation and invasion. Although both ARA70 alpha and ARA70 beta functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70 beta overexpression, in contrast to ARA70 alpha, promoted prostate cancer cellular proliferation and invasion through Matrigel. Interestingly, genome-wide expression profiling of cells expressing ARA70 beta revealed an increase in the expression of genes involved in the control of cell division and adhesion, compatible with a role for ARA70 beta in proliferation and invasion. Consistent with its function in promoting cell growth and invasion, ARA70 beta expression was increased in prostate cancer. Our findings implicate ARA70 beta as a regulator of tumor cell growth and metastasis by affecting gene expression
— id: 76451, year: 2008, vol: 172, page: 225, stat: Journal Article,

The Heterochromatin Protein 1 Family is Regulated in Prostate Development and Cancer
Shapiro, Ellen; Huang, Hongying; Ruoff, Rachel; Lee, Peng; Tanese, Naoko; Logan, Susan K
2008 Apr 22;179(6):2435-2439, Journal of urology
PURPOSE: The HP1 family of evolutionarily conserved proteins regulates heterochromatin packaging, in addition to a less defined role in the regulation of euchromatic genes. To examine the possible role of HP1 proteins in fetal prostate development and prostate cancer the protein expression of HP1alpha, beta and gamma was evaluated in human archival tissue. MATERIALS AND METHODS: Tissue sections from human prostate cancer and fetal prostate were examined using antibodies against HP1 isoforms to evaluate HP1 modulation in cancer and development. Western blot analysis of HP1 proteins was also performed in extracts of cultured prostate cancer cells. RESULTS: HP1alpha, beta and gamma are differentially regulated in various cellular compartments in prostate development. HP1alpha is not expressed at 14 or 24 weeks of prostate development but it is expressed in adult prostate tissue. HP1beta is highly expressed at 14 and 24 weeks, and it appears predominantly in epithelial cells compared to HP1gamma, which is expressed at equal levels in epithelial and stromal cells. All 3 HP1 isoforms show altered expression in prostate cancer compared to that in normal adult prostate tissue. CONCLUSIONS: HP1 proteins are tightly regulated during prostate development. In the adult prostate HP1alpha, beta and gamma antibodies detect high levels of HP1 antigen in a contiguous layer of epithelial cells. However, the detection of HP1 in prostate cancer ranges from undetectable to inconsistent staining of noncontiguous epithelial cells
— id: 78573, year: 2008, vol: 179, page: 2435, stat: Journal Article,

Expression of intracellular domain of notch1 (ICN1), Lef-1, and phosphorylated STAT3 (pSTAT3) in angioimmunoblastic T-cell lymphoma
Zhang, XM; Li, X; Chiriboga, L; Chandra, P; Lee, P; Ibrahim, S
2008 JAN ;21(2):284A-284A, Modern pathology
— id: 75921, year: 2008, vol: 21, page: 284A, stat: Journal Article,

Expression of intracellular domain of notchl (ICN1), lef-1, and phosphorylated STAT3 (Pstat3) in angioimmunoblastic T-cell lymphoma
Zhang, XM; Li, X; Chiriboga, L; Chandra, P; Lee, P; Ibrahim, S
2008 JAN ;88(2):284A-284A, Laboratory investigation
— id: 75942, year: 2008, vol: 88, page: 284A, stat: Journal Article,

Altered expression of androgen receptor target genes in prostate cancer
Adler, Michael; Lee, Peng
2007 ;1:29-29, Probe: the publication of research on biomedical endeavors
— id: 75321, year: 2007, vol: 1, page: 29, stat: Journal Article,

Radiographic determination of tissue thickness in paraffin blocks: application to the construction of tissue microarrays
Kong, Xiangtian; Zhao, Yan; Ksionsk, Marti; Zhou, Meisheng; Walden, Paul; Bosland, Maarten; Pei, Zhiheng; Lee, Peng; Melamed, Jonathan
2007 Mar;15(1):108-112, Applied immunohistochemistry & molecular morphology
The determination of tissue thickness in paraffin blocks in the histology laboratory has been largely based on visual estimates. More accurate methods are required for the construction of tissue microarrays (TMAs) to assure a greater yield of cores in sections through the TMA block. We describe an accurate radiographic method to determine tissue thickness in donor paraffin blocks and have validated its application to TMA construction. Individual radiographic analysis was performed on paraffin donor blocks used for the construction of TMAs for determination of donor block tissue thickness. Consecutive numbered slide sections through the TMA block were then examined for the presence or loss of cores in the 150th TMA slide (from the final third of the TMA block) and correlated with the thickness of the individual donor blocks determined radiographically. At the 150th TMA slide, 202 of 1340 cores (15.1%) were depleted. Radiographic measurement showed a greater thickness of the donor paraffin block tissue (2.02 mm) corresponding to the retained cores as compared with the donor tissue (1.54 mm) of the depleted cores (P < 0.001). With progressive slide sections through a TMA block, the retention of tissue cores shows a significant correlation with donor block tissue thickness. Radiographic determination of tissue thickness in donor paraffin blocks can be used in TMA construction. Prior knowledge of tissue thickness in TMA construction can prompt compensatory steps that can enhance the yield of valuable samples and assure sufficient numbers of adequate cores for statistical analysis in biomarker evaluations
— id: 73238, year: 2007, vol: 15, page: 108, stat: Journal Article,

Diagnosis and management of cancer using serologic tumor markers
Lee P; Pincus MR; McPherson MA
Henry's clinical diagnosis and management by laboratory methods Philadelphia : Saunders Elsevier, 2007,
— id: 4027, year: 2007, vol: , page: 1353, stat: Chapter,

The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors
Liang, John J; Wang, Zhengxin; Chiriboga, Luis; Greco, M Alba; Shapiro, Ellen; Huang, Hongying; Yang, Ximing J; Huang, Jiaoti; Peng, Yi; Melamed, Jonathan; Garabedian, Michael J; Lee, Peng
2007 May;177(5):1918-1922, Journal of urology
PURPOSE: The role of androgen receptor coactivators in testicular development and cancer formation is unclear. p44/Mep50 was identified as an androgen receptor coactivator that functions in a complex with protein arginine methyltransferase 5. We studied the expression of p44 and protein arginine methyltransferase 5 in developing fetal testis and adult testicular tumors, including seminomas and Leydig cell tumors. MATERIALS AND METHODS: A total of 30 human fetal testes from abortuses at a gestational age of 10 to 40 weeks, 33 human seminomas and 11 human Leydig cell tumors were retrieved from the archives of the departments of pathology. Immunohistochemistry was performed with affinity purified p44 and IgG purified protein arginine methyltransferase 5 polyclonal antibodies. RESULTS: Protein arginine methyltransferase 5 and p44 were expressed predominantly as nuclear proteins in fetal Leydig cells and human adult nonneoplastic testes, including germ cells and Leydig cells, while they were expressed in the cytoplasm of germ cells of the fetal testis. Expression was strongest in the fetal testis during the second trimester. Compared to adult nonneoplastic testes, human seminoma and Leydig tumor cells showed a marked decrease in nuclear expression of p44 and protein arginine methyltransferase 5 with a concomitant marked increase in cytoplasmic expression of these proteins. Furthermore, average testicular size was increased by 29% in p44(+/-) heterzygotic mice. CONCLUSIONS: These results suggest distinct functions of the nuclear and the p44/protein arginine methyltransferase 5 complexes in the developing fetal testis and in the oncogenesis of testicular tumors. Further studies are needed to confirm the functional relevance of these findings
— id: 72417, year: 2007, vol: 177, page: 1918, stat: Journal Article,

Expression of HOXA5 and HOXA9 genes in ductal carcinoma of human breast
Wang, J; Chiriboga, L; Yee, H; Cangiarella, J; Lee, P; Sun, W
2007 OCT ;128(4):688-688, American journal of clinical pathology
— id: 74340, year: 2007, vol: 128, page: 688, stat: Journal Article,

A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas
Wang, Tongsheng; Zhang, Xinmin; Obijuru, Laura; Laser, Jordan; Aris, Virginie; Lee, Peng; Mittal, Khush; Soteropoulos, Patricia; Wei, Jian-Jun
2007 Jan 22;46(4):336-347, Genes, chromosomes & cancer
Human uterine leiomyomas (ULMs) are the most common neoplasms of women. Many genes are dysregulated in ULMs and some of this dysregulation may be due to abnormal expression of micro-RNAs (miRNAs). In this study, 55 ULMs and matched myometrium were collected from 41 patients for microarray-based global miRNA expression analysis. Of 206 miRNAs examined, 45 miRNAs were significantly up- or down-regulated in ULMs in comparison to the matched myometrium (P < 0.001). The top five dysregulated miRNAs in ULMs are the let-7 family, miR-21, miR-23b, miR-29b, and miR-197. Four polycistronic clusters of miRNAs were either up- or down-regulated, but not in a mixed pattern, indicative of coordinated regulation of these miRNAs. Significance analysis revealed that subsets of miRNAs were strongly associated with tumor sizes and race. By prediction analysis we identified some important tumorigenic genes previously identified in ULMs that may be targeted by the dysregulated miRNAs. HMGA2 was identified as one of target genes of the let-7 family of miRNAs and has been found to be suppressed by let-7 in vitro. (This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.) (c) 2007 Wiley-Liss, Inc
— id: 70177, year: 2007, vol: 46, page: 336, stat: Journal Article,

The expression of cFLIP in human fetal testis
Wen, YH; Sarita-Reyes, C; Chiriboga, L; Yee, H; Lee, P; Greco, MA
2007 FEB ;87(2):204-204, Laboratory investigation
— id: 70928, year: 2007, vol: 87, page: 204, stat: Journal Article,

Differences in clinicopathologic features of prostate cancer between black and white patients treated in the 1990s and 2000s
Berger, Aaron D; Satagopan, Jaya; Lee, Peng; Taneja, Samir S; Osman, Iman
2006 Jan;67(1):120-124, Urology
OBJECTIVES: We have previously reported on the disparity in the clinicopathologic features of prostate cancer between black and white patients at our equal-access institution during the 1990s. The goal of this study was to determine whether the worse clinicopathologic features of prostate cancer in black patients have persisted in the 2000s. METHODS: We examined 362 men (224 black and 138 white) treated with radical prostatectomy at the Veterans Affairs Medical Center in New York. We compared the clinicopathologic variables between 227 patients treated during the 1990s (group 1) and 135 treated in the 2000s (group 2). RESULTS: In group 1, black patients were significantly younger (P < 0.001) and had a greater prostate-specific antigen (PSA) level (P = 0.001), Gleason score (P = 0.005), and stage (P = 0.03) than white patients. In group 2, black patients continued to have significantly greater PSA levels (P = 0.04) and Gleason scores (P = 0.005) than white patients. Comparing only the black patients, those in group 2 had significantly lower PSA levels (P < 0.001) and stage (P = 0.03), but had worse Gleason scores (P = 0.03) than those in group 1. On multivariate analysis, black patients were significantly more likely to have a worse Gleason score (P = 0.005) than white patients. CONCLUSIONS: Our data have demonstrated a narrowing of the differences in pathologic stage between black and white patients in the 2000s. However, black men have continued to have worse Gleason scores and greater PSA levels than white patients. These findings suggest that there may be different patterns of molecular alterations in black men that may contribute to the poor tumor differentiation. Additional research is underway to better characterize these underlying molecular mechanisms
— id: 68181, year: 2006, vol: 67, page: 120, stat: Journal Article,

Role of desumoylation in the development of prostate cancer
Cheng, Jinke; Bawa, Tasneem; Lee, Peng; Gong, Limin; Yeh, Edward T H
2006 Aug;8(8):667-676, Neoplasia
SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development
— id: 68827, year: 2006, vol: 8, page: 667, stat: Journal Article,

Novel mutations of epidermal growth factor receptor in localized prostate cancer
Douglas, Diah A; Zhong, Hong; Ro, Jae Y; Oddoux, Carole; Berger, Aaron D; Pincus, Matthew R; Satagopan, Jaya M; Gerald, William L; Scher, Howard I; Lee, Peng; Osman, Iman
2006 ;11:2518-2525, Frontiers in biosciences
We recently demonstrated that EGFR protein overexpression is more common in African American (AA) prostate cancer patients compared to Caucasian patients. We further examine EGFR dysregulation by determining EGFR mutation status in the tyrosine kinase (TK) domain in prostate cancer patients of different ethnicity. Normal and tumor DNA from 89 radical prostatectomy cases were studied for mutations in the EGFR TK domain using genomic DNA sequencing. We identified 4 novel missense mutations in exons 19, 20 and 21 of EGFR TK domain: 3 in Koreans and 1 in Caucasian but none in AA. We also identified 5 distinct synonymous DNA sequence changes, which did not alter the encoded amino acid, in exons 20 and 21 in 31/89 (35%) patients. Interestingly, these synonymous sequence changes were not observed in normal DNA in 7(23%) patients, indicating the presence of de novo somatic mutation to a new synonymous sequence. Our data reveal that EGFR missense mutation in the TK domain occurs in localized prostate cancer. Our data also demonstrate the presence of somatic mutation to a new synonymous sequence in a subset of patients. Larger population-based studies are required to define the association between EGFR mutations and the ethnic background of patients
— id: 64213, year: 2006, vol: 11, page: 2518, stat: Journal Article,

Myxoid lipoadenoma of parathyroid gland: a case report and literature review
Fischer, Ingeborg; Wieczorek, Rosemary; Sidhu, Gurdip S; Pei, Zhiheng; West, Brian; Lee, Peng
2006 Oct;10(5):294-296, Annals of diagnostic pathology
Myxoid lipoadenoma of the parathyroid gland is a rare variant of parathyroid adenoma. We present the case of a 40-year-old man with asymptomatic hypercalcemia who underwent surgical removal of a parathyroid adenoma. Histologically, the tumor consisted of monomorphous round-to-oval chief cells arranged in several architectural patterns including solid sheet-like, trabecular, and follicular. The tumor stroma was prominently myxoid with interspersed mature adipose tissue. Immunohistochemistry confirmed expression of thyroid transcription factor and parathyroid hormone by all tumor cells and a low proliferation rate with a Ki-67 labeling index of at most 5%. Although the lesion exhibited characteristics that have been previously associated with 'atypical parathyroid adenoma,' such as dense fibrous bands within the tumor and a trabecular growth pattern, there was no further evidence, neither histologically nor clinically, for malignant behavior of the tumor
— id: 68682, year: 2006, vol: 10, page: 294, stat: Journal Article,

Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland
Gao, Shen; Wang, Hua; Lee, Peng; Melamed, Jonathan; Li, Caihong X; Zhang, Fahao; Wu, Hong; Zhou, Liran; Wang, Zhengxin
2006 Jun;36(3):463-483, Journal of molecular endocrinology
Androgen receptor (AR) is a ligand-activated transcription factor that mediates the action of androgens and is essential for the growth, function, and cell differentiation of the prostate gland. Here, we demonstrated that the prostate apoptosis response factor-4 (par-4) functions as a novel AR coactivator. Par-4 physically interacted with the DNA-binding domain of AR, enhanced AR interaction with DNA, and increased AR-dependent transcription. Par-4 enhanced the c-FLIP promoter activity and was recruited on to the c-FLIP gene in the presence of androgens, and the dominant-negative par-4 decreased c-FLIP expression. These results suggest that, in addition to its proapoptotic function, par-4 acts as a novel transcription cofactor for AR to target c-FLIP gene expression. In addition, we demonstrated that loss of c-FLIP expression was essential for castration-induced apoptosis in the prostate gland and that enhanced c-FLIP expression was associated with prostate cancer progression to the androgen-resistant stage. Our data shed light on a transcription-mediated mechanism for the effects of the AR pathway on cell survival and apoptosis
— id: 64212, year: 2006, vol: 36, page: 463, stat: Journal Article,

Loss of neutral endopeptidase and activation of protein kinase B (Akt) is associated with prostate cancer progression
Osman, Iman; Dai, Jie; Mikhail, Maryann; Navarro, Daniel; Taneja, Samir S; Lee, Peng; Christos, Paul; Shen, Ruoqian; Nanus, David M
2006 Dec 1;107(11):2628-2636, Cancer
BACKGROUND: Neutral endopeptidase (NEP) is a cell-surface peptidase that can regulate the activation of Akt kinase through catalytic-dependent and independent mechanisms. NEP expression is absent in approximately 50% of prostate cancers. The authors investigated whether NEP loss in vivo would result in Akt phosphorylation and potentially contribute to prostate cancer progression by examining the interaction of NEP, Akt, and phosphatase and tensin homolog (PTEN) in a prostate xenograft model and in clinical specimens from patients with prostate cancer. METHODS: Using a tetracycline-repressible expression system to express NEP in a tumor animal xenograft model, the effects of NEP were tested on tumor growth, Akt phosphorylation, and PTEN expression. The clinical relevance of NEP, phosphorylated Akt, and PTEN protein expression also was investigated in 204 patients who had undergone radical prostatectomy. RESULTS: The results indicated that the induction of NEP expression inhibited established xenograft tumor growth, diminished Akt phosphorylation, and increased PTEN protein levels. In humans, prostate cancers with complete loss of NEP expression were significantly more likely to express phosphorylated Akt (P = .02). Moreover, patients who had prostate cancers with concomitant loss of NEP and expression of phosphorylated Akt had an increased, independent risk of prostate-specific antigen (PSA) recurrence (P = .03). In the study cohort, loss of PTEN protein expression did not correlated significantly with phosphorylated Akt or with patients' clinical outcome. CONCLUSIONS: The findings from this investigation demonstrated that NEP loss leads to Akt activation and contributes to the clinical progression of prostate cancer
— id: 94952, year: 2006, vol: 107, page: 2628, stat: Journal Article,

Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells
Zhou, Liran; Wu, Hong; Lee, Peng; Wang, Zhengxin
2006 Oct;37(2):283-300, Journal of molecular endocrinology
Various cofactors have been shown to regulate androgen receptor (AR) transactivation, but their physiological functions in the AR pathway and prostate tumorigenesis are undefined. Here, we found that AR cofactor (p44) translocation from the nucleus to the cytoplasm in prostate epithelial cells (ECs) is associated with prostate tumorigenesis. The forced nuclear localization of p44 inhibited prostate cancer cell growth by G1 cell-cycle arrest. Consistently, mice lacking one allele of the p44 gene developed prostatic hyperplasia. Therefore, p44 is required for proper expression of AR-target genes to maintain the differentiation of prostate ECs, and p44 translocation from the nucleus into the cytoplasm in prostate cancer cells or loss of one allele in mouse results in excessive prostate EC proliferation
— id: 68826, year: 2006, vol: 37, page: 283, stat: Journal Article,

EXPRESSION OF ANDROGEN RECEPTOR ASSOCIATED PROTEIN 55 (ARA55) IN THE DEVELOPING HUMAN FETAL PROSTATE
Cai, Guoping; Huang, Hongying; Shapiro, Ellen; Zhou, Holly; Yeh, Shuyuan; Melamed, Jonathan; Greco, M Alba; Lee, Peng
2005 Jun;173(6):2190-2193, Journal of urology
PURPOSE:: Development and differentiation of the human fetal prostate are androgen dependent and follow a specific pattern of solid bud-ductal morphogenesis, which involves stromal-epithelial interactions. Androgen receptor associated protein 55 (ARA55) an androgen receptor coactivator localized in stromal cells, binds to androgen receptor (AR) and regulates androgen receptor translocation and transcriptional activity. We investigated whether ARA55 has a role in human prostate development. MATERIALS AND METHODS:: ARA55 expression was examined in 25 human prostates from fetuses at gestational ages 10 to 40 weeks and compared to the expression of 34betaE12 (a basal cell marker), smooth muscle actin, desmin (a smooth muscle marker), vimentin (a mesenchymal marker) and Ki-67 (a proliferation marker) by immunohistochemistry. RESULTS:: Prostatic epithelium appeared as solid epithelial buds from the urogenital sinus. It underwent arborization and ductal differentiation from the center to the periphery. ARA55 was expressed in stromal cells with a zonal pattern, primarily in the peripheral zone surrounding the noncanalized acini. Most cells in solid buds were positive for 34betaE12, while only basal layer cells in the centrally located epithelial ducts stained with 34betaE12. Solid buds also had a higher proliferation index than ducts. In addition, ARA55 expressing stromal cells but not ARA55 negative stromal cells showed smooth muscle differentiation. CONCLUSIONS:: The intimate relationship between ARA55 expressing stromal cells and mitotically active, noncanalized acini suggests that ARA55 has a role in the stromal-epithelial interaction involved in fetal prostate development
— id: 51801, year: 2005, vol: 173, page: 2190, stat: Journal Article,

The androgen receptor directly targets the c-FLIP gene to promote the androgen-independent growth of prostate cancer cells
Gao, Shen; Lee, Peng; Wang, Hua; Gerald, William; Adler, Michael; Zhang, Liying; Wang, Yun-Fang; Wang, Zhengxin
2005 Jul;19(7):1792-1802, Molecular endocrinology
Androgens provide survival signals to prostate epithelial cells, and androgen ablation induces apoptosis in the prostate gland. However, the molecular mechanisms of actions of the androgen-signaling pathway in these processes are not fully understood. Here, we report that androgens induced expression of the cellular FLIP (c-FLIP) gene, which is a potent inhibitor of Fas/FasL-mediated apoptosis. The androgen receptor (AR) was recruited to the promoter of the c-FLIP gene in the presence of androgens. We found that c-FLIP promoter contained multiple functional androgen response elements (AREs). In addition, we show that c-FLIP overexpression accelerated progression to androgen independence by inhibiting apoptosis in LNCaP prostate tumors implanted in nude mice. Our results suggest that AR affects survival and apoptosis of prostate cells through regulation of the c-FLIP gene in response to androgens
— id: 48747, year: 2005, vol: 19, page: 1792, stat: Journal Article,

Adenomatoid tumor of the adrenal gland: A clinicopathologic study of 3 cases
Garg, Karuna; Lee, Peng; Ro, J Y; Qu, Zhenhong; Troncoso, Patricia; Ayala, Alberto G
2005 Feb;9(1):11-15, Annals of diagnostic pathology
Abstract Adenomatoid tumors are relatively uncommon benign neoplasms of mesothelial origin, usually occurring in the male and female genital tracts. Rare extragenital adenomatoid tumors have been identified in the adrenal glands, heart, mesentery, pleura, and lymph nodes. In the adrenal gland, adenomatoid tumors may pose a diagnostic challenge. The differential diagnosis includes adrenocortical carcinoma and metastatic carcinoma, especially signet ring cell carcinoma. Because of its glandular pattern, an adenomatoid tumor may be confused with an adenocarcinoma. We present 3 cases of adrenal adenomatoid tumors, including one with a concurrent large hemorrhagic vascular adrenal cyst. The adenomatoid tumors were unilateral, appeared solid and white, and varied from 1.7 to 4.2 cm in diameter. They occurred in 3 male patients aged 33, 33, and 46 years. One patient presented with abdominal pain due to the presence of a concurrent large adrenal cyst. The tumor was an incidental radiological finding in another case and was discovered during the course of a workup for hypertension in the third case. The light microscopic appearances were consistent with those of typical adenomatoid tumors. Immunohistochemical stains for calretinin and cytokeratin 5/6 were positive, confirming the tumors' mesothelial origin. Ultrastructural studies performed in 2 cases revealed microvilli and desmosomes. Follow-up showed no evidence of recurrence or metastasis. In our experience, the key to the diagnosis of this rare benign tumor is to consider adenomatoid tumor in the differential diagnosis of any glandular tumor occurring in the adrenal gland
— id: 48054, year: 2005, vol: 9, page: 11, stat: Journal Article,

Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer
Lee, Peng; Rosen, Daniel G; Zhu, Changcheng; Silva, Elvio G; Liu, Jinsong
2005 Mar;96(3):671-677, Gynecologic oncology
OBJECTIVE: Receptors for estrogen (ER), progesterone (PR), or androgen (AR) are predictive and prognostic markers of malignancy of multiple endocrine organs, including endometrial and breast cancer. However, the role of ERs, PRs, or ARs in the carcinogenesis of ovarian cancer, another sex hormone-dependent malignancy, is still controversial despite numerous studies that have attempted to determine their role. The disagreement in the findings may result from the fact that the numbers of tumor samples in studies have been small and that different immunohistochemical methods have been used that can introduce variation in the scoring of the histology. We therefore examined the pattern of expression of ERs, PRs, and ARs in a large number of samples of primary ovarian carcinoma by using a tissue microarray technique. METHODS: We constructed a tissue microarray with 322 samples of primary ovarian carcinoma obtained at surgery performed at The University of Texas M. D. Anderson Cancer Center between 1990 and 2000. Immunohistochemistry studies were performed by using the immunoperoxidase technique against primary antibodies (ER, PR, and AR). RESULTS: ERs, PRs, and ARs were differently expressed in different histotypes of ovarian cancer: ERs were expressed in 77.3% of all cases but more highly expressed in serous and endometrioid types; PRs were expressed in 26.2% of all cases but most highly expressed in the endometrioid type < 64.2%; and ARs were expressed in 43.7% of all cases but were most highly expressed in serous (47.5%) carcinomas. Of particular importance, the expression of PRs, but not ERs or ARs, was associated with better survival (P < 0.0001) in univariate and multivariate analyses. CONCLUSIONS: The PR is an independent marker, with its overexpression associated with a favorable prognosis in women with ovarian cancer
— id: 48222, year: 2005, vol: 96, page: 671, stat: Journal Article,

Expression of androgen receptor coactivator ARA70/ELE1 in androgenic alopecia
Lee, Peng; Zhu, Chang-Cheng; Sadick, N S; Diwan, A Hafeez; Zhang, Peter S; Liu, Jinsong S; Prieto, Victor G
2005 Sep;32(8):567-571, Journal of cutaneous pathology
Background: Androgens have been implicated in androgenic alopecia as evidenced by the increased cutaneous expression of androgen receptor (AR), 5alpha-reductase, and decreased aromatase. Abnormalities of the AR-signal transduction pathway probably participate in the development of androgenic alopecia. ARA70/ELE1 is an AR coactivator with two isoforms, one full-length form (ARA70alpha/ELE1alpha), and an internally deleted form (ARA70beta/ELE1beta). We decided to examine the cutaneous expression of both isoforms in male androgenic alopecia. Methods: Formalin-fixed, paraffin-embedded tissue sections from seven subjects with androgenic alopecia with matched punch biopsies from non-balding and balding areas were examined by in situ hybridization. Results: Expression of at least one of the two probes for ARA70/ELE1 was present in all phases of the hair-growth cycle in all epithelial hair structures except for the inner root sheath. The dermal papilla and hair bulb expressed only the short (beta) but not the long (alpha) form of ARA70/ELE1. In situ labeling for ARA70beta/ELE1beta was weaker in the dermal papilla of balding recipient areas than those from donor ones. Conclusions: Our data further support that the hair growth is regulated by androgens. The differential expression pattern of ARA70/ELE1 suggests that this key androgen receptor coactivator is involved in androgenic alopecia. Lee P, Zhu C-C, Sadick NS, Diwan AH, Zhang PS, Liu JS, Prieto VG. Expression of androgen receptor coactivator ARA70/ELE1 in androgenic alopecia
— id: 57668, year: 2005, vol: 32, page: 567, stat: Journal Article,

Cell-specific regulation of androgen receptor phosphorylation in vivo
Taneja, Samir S; Ha, Susan; Swenson, Nicole K; Huang, Hong Ying; Lee, Peng; Melamed, Jonathan; Shapiro, Ellen; Garabedian, Michael J; Logan, Susan K
2005 Dec 9;280(49):40916-40924, Journal of biological chemistry
The biological ramifications of phosphorylation of the androgen receptor (AR) are largely unknown. To examine the phosphorylation of AR at serine 213, a putative substrate for Akt, a phosphorylation site-specific antibody was generated. The use of this antibody indicated that AR Ser-213 is phosphorylated in vivo and that phosphorylation is tightly regulated in a cell type-specific manner. Furthermore, Ser-213 phosphorylation took place with rapid kinetics and was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. Phosphorylation occurred in response to R1881 and dihydrotestosterone but weakly if at all in response to testosterone. It did not occur in response to AR antagonists or growth factor stimulation in the absence of an AR agonist. Transcription assays using an AR-responsive reporter gene construct showed that activated phosphatidylinositol 3-kinase inhibited transcription mediated by wild type AR but not that of a mutant AR variant (S213A), which could not be phosphorylated at Ser-213. By immunohistochemistry, the AR Ser(P)-213 antigen was detected in prostate epithelial but not stromal cells despite the fact that an antibody recognizing both phosphorylated and non-phosphorylated forms of AR demonstrates that AR is present in both cell types as expected. In fetal tissue the AR-Ser(P)-213 antigen was present in epithelial cells of the urogenital sinus when endogenous androgen levels were high and activated Akt was prevalent, but absent at a later stage of development when endogenous androgen levels were low and Akt activation was minimal. Immunoreactivity was evident in differentiated cells lining the lumen of the urogenital sinus but not in rapidly dividing, Ki67 positive cells within the developing prostate or stromal tissue, suggesting that site-specific phosphorylation of AR Ser-213 by cellular kinases occurs in a non-proliferating cellular milieu
— id: 61359, year: 2005, vol: 280, page: 40916, stat: Journal Article,

Proteomic analysis of global alteration of protein expression in squamous cell carcinoma of the esophagus
Zhou, Ge; Li, Hongmei; Gong, Yi; Zhao, Yingxin; Cheng, Jingke; Lee, Peng; Zhao, Yingming
2005 Sep;5(14):3814-3821, Proteomics
Squamous cell carcinoma of the esophagus (ESCC), a major subtype of esophageal carcinoma, is one of the aggressive cancers with worst prognosis in the world. The dismal outcome of ESCC is attributed to multiple reasons including its aggressive nature, largely unknown molecular mechanism of its progression, and the lack of biomarkers for early detection and effective prediction of its clinical behavior. To identify proteins with prognostic and/or predictive value, we applied a proteomics strategy to quantify proteins differentially expressed in ESCC using matched samples of carcinoma and adjacent normal epithelial cells. The analysis led to identification of 28 proteins aberrantly expressed in cancer cells with changes of at least three-fold in ESCC relative to normal squamous epithelial cells. These changes represent functional alterations of essential proteins for normal cellular physiology, accounting for many cellular changes involved in development of ESCC, including cell transformation, loss of differentiation, tumor growth, apoptosis, tumor invasion, and cell metabolism. The differentially expressed proteins shed new insights on the mechanism of tumorigenesis and provide candidate biomarkers for early detection of ESCC
— id: 57699, year: 2005, vol: 5, page: 3814, stat: Journal Article,

Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer
Hu, Yueh-Chiang; Yeh, Shuyuan; Yeh, Shauh-Der; Sampson, Erik R; Huang, Jiaoti; Li, Peng; Hsu, Cheng-Lung; Ting, Huei-Ju; Lin, Hui-Kuan; Wang, Liang; Kim, Eungseok; Ni, Jing; Chang, Chawnshang
2004 Aug 6;279(32):33438-33446, Journal of biological chemistry
Androgen receptor (AR)-associated coregulator 70 (ARA70) was the first identified AR coregulator. However, its molecular mechanism and biological relevance to prostate cancer remain unclear. Here we show that ARA70 interacts with and promotes AR activity via the consensus FXXLF motif within the ARA70-N2 domain (amino acids 176-401). However, it does not promote AR activity via the classic LXXLL motif located at amino acids 92-96, although this classic LXXLL motif is important for ARA70 to interact with other receptors, such as PPARgamma. The molecular mechanisms by which ARA70 enhances AR transactivation involve the increase of AR expression, protein stability, and nuclear translocation. Furthermore, ARA70 protein is more frequently detected in prostate cancer specimens (91.74%) than in benign tissues (64.64%, p < 0.0001). ARA70 expression is also increased in high-grade prostate cancer tissues as well as the hormone-refractory LNCaP xenografts and prostate cancer cell lines. Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer. Because ARA70-N2 containing the AR-interacting FXXLF motif without coactivation function can suppress HF-enhanced AR transactivation in the hormone-refractory LNCaP cells, using the ARA70-N2 inhibitory peptide at the hormone refractory stage to battle the HF withdrawal syndrome may become an alternative strategy to treat prostate cancer
— id: 44516, year: 2004, vol: 279, page: 33438, stat: Journal Article,

Role of androgen receptor cofactors in human prostrate cancer
Lee P; Wang ZX
Handbook of immunohistochemistry and in situ hybridization of human carcinomas Amsterdam : Elsevier, 2004,
— id: 3327, year: 2004, vol: 2, page: 409, stat: Chapter,

Racial disparity of epidermal growth factor receptor expression in prostate cancer
Shuch, Brian; Mikhail, Maryann; Satagopan, Jaya; Lee, Peng; Yee, Herman; Chang, Caroline; Cordon-Cardo, Carlos; Taneja, Samir S; Osman, Iman
2004 Dec 1;22(23):4673-4677, Journal of clinical oncology
PURPOSE: The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors. PATIENTS AND METHODS: We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically. RESULTS: EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION: Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents
— id: 46900, year: 2004, vol: 22, page: 4673, stat: Journal Article,

Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription
Hosohata, Keiko; Li, Peng; Hosohata, Yoshiaki; Qin, Jun; Roeder, Robert G; Wang, Zhengxin
2003 Oct;23(19):7019-7029, Molecular & cellular biology
The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue
— id: 42675, year: 2003, vol: 23, page: 7019, stat: Journal Article,

Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast
Xu, Ruliang; Feiner, Helen; Li, Peng; Yee, Herman; Inghirami, Giorgio; Delgado, Yara; Perle, Mary Ann
2003 Nov;127(11):1458-1464, Archives of pathology & laboratory medicine
CONTEXT: Medullary carcinoma (MC) is a special type of breast cancer that has a better prognosis than atypical medullary carcinoma (AMC) and high-grade invasive ductal carcinoma (HGIDC) with prominent lymphocytic infiltrates. What accounts for the different clinical courses of these carcinomas, despite their similar histology, is unknown. To address this issue, we performed a comparative study of amplification and overexpression of HER-2/neu and expression of several other important biochemical markers (p53, MIB1, and estrogen receptor [ER]/progesterone receptor [PR]) in these 3 cancer groups. OBJECTIVE: To evaluate HER-2/neu, p53, MIB1, and ER/PR as markers in the differential diagnosis of MC, AMC, and HGIDC.Design.-Nine cases of MC, 13 cases of AMC, and 16 cases of HGIDC with prominent lymphocytic infiltrates were identified according to strict histologic criteria. All tests were performed on formalin-fixed, paraffin-embedded archival tissues. HER-2/neu gene amplification was examined by fluorescence in situ hybridization using PathVysion HER-2 DNA probes. Expression of HER-2/neu, p53, MIB1, and ER/PR was detected by immunohistochemistry. chi2 and Student t tests were applied for statistical analyses. RESULTS: None of 9 cases of MC examined had either amplification or overexpression of HER-2/neu (0%). In contrast, HER-2/neu amplification was observed in AMC (46%, P <.025) and HGIDC (56%, P <.005). All 3 categories of tumors had similar percentages of expression of p53 (78% of MC, 77% of AMC, and 69% of HGIDC) and MIB1 (89% of MC, 92% of AMC, and 94% of HGIDC). Immunostaining for ER/PR was rarely positive in either MC or AMC, and there were no significant differences of expression of ER/PR between these 2 lesions (P >.05). However, the expression rate of ER/PR (31%/44%) in HGIDC is higher than in both MC (P =.05) and AMC (P =.01). CONCLUSIONS: Medullary carcinoma of breast is distinct from AMC and HGIDC with prominent lymphocytic infiltrates in amplification and overexpression of HER-2/neu. This difference may account for its different clinical and biological behavior, and may potentially aid in diagnosis and management of these groups of patients
— id: 38864, year: 2003, vol: 127, page: 1458, stat: Journal Article,

Wilms' tumor in adults: aspiration cytology and cytogenetics
Li, Peng; Perle, Mary Ann; Scholes, John V; Yang, Grace C H
2002 Feb;26(2):99-103, Diagnostic cytopathology
The fine-needle aspiration cytologic findings of Wilms' tumor occurring in a 20-yr-old female patient and a 35-yr-old male patient showing blastemal, spindled sarcomatous and rare epithelial components are reported. The male patient had the typical presentation of renal mass with metastasis to lung and pleura, whereas the female patient had an unusual presentation with the tumor originated from the subcapsular nephrogenic zone of the kidney, extending into the liver without invasion into the renal cortex. Cytogenetic analysis of this case identified: 90, XXXX, +2x3-4, -5, -15, -16, -17, -17, i (17)(q10) x2. This finding may represent a genetic change associated with Wilms' tumor of older pediatric and young adult patients. To the best of our knowledge, this case is the sixth case with cytogenetic study and the first case revealing isochromosome 17q of an adult Wilms' tumor
— id: 27218, year: 2002, vol: 26, page: 99, stat: Journal Article,

Epithelioid Gastrointestinal Stromal Tumor of the Stomach with Liver Metastases in a 12-Year-old Girl: Aspiration Cytology and Molecular Study
Li, Peng; Wei, Jianjun; West, A Brian; Perle, MaryAnn; Greco, M Alba; Yang, Grace C H
2002 Jul-Aug;5(4):386-394, Pediatric & developmental pathology
Gastrointestinal stromal tumor (GIST), a stromal tumor of the gastrointestinal tract defined as CD117 (c-kit)-positive neoplasm, occurs primarily in adults. GIST with CD117 (c-kit) mutation and certain cytogenetic abnormalities is associated with malignancy, though a definite relationship between prognosis and molecular alterations remains to be elucidated. We report the cytologic features of an epithelioid GIST arising in the stomach of a child and metastatic to the liver, and the molecular mutational analysis of both the primary gastric tumor and the liver metastasis. Literature of pediatric GISTs was also reviewed. Fine needle aspiration of the liver metastasis, processed by Ultrafast Papanicolaou stain, showed fragments of cohesive small epithelioid cells with bland oval nuclei and unipolar cytoplasm transected by capillaries. Immunohistochemically, all nodules in the stomach and liver expressed CD117 (c-kit). Interestingly, some of the gastric tumor clusters were uniformly CD34 positive, whereas others were uniformly CD34 negative, suggesting heterogeneity of tumor clones. The presence of neurosecretory granules further subtyped the tumor into gastric autonomic nerve tumor (GANT). Molecular mutational analysis, performed in both the gastric tumor and the liver metastasis, showed no sequence abnormality in exons 9, 11, and 13 of CD117 (c-kit). Cytogenetic study revealed normal karyotype. These features might suggest a different molecular mechanism leading to malignancy in certain GISTs arising in children
— id: 32275, year: 2002, vol: 5, page: 386, stat: Journal Article,

Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer
Li, Peng; Yu, Xin; Ge, Kai; Melamed, Jonathan; Roeder, Robert G; Wang, Zhengxin
2002 Oct;161(4):1467-1474, American journal of pathology
The androgen receptor (AR), a ligand-activated transcription factor of the steroid receptor superfamily, plays an important role in normal prostate growth and in prostate cancer. The recent identification of various AR co-factors prompted us to evaluate their possible roles in prostate tumorigenesis. To this end, we analyzed the expression of AR and eight of its co-factors by quantitative in situ RNA hybridization in 43 primary prostate cancers with different degrees of differentiation. Our results revealed nearly constant expression of AR and heterogeneous expression of AR co-factors, with increased expression of PIAS1 and Ran/ARA24, decreased expression of ELE1/ARA70, and no change in TMF1/ARA160, ARA54, SRC1, or TRAP220. Interestingly, whereas TMF1/ARA160, ELE1/ARA70, ARA54, RAN/ARA24, and PIAS1 were preferentially expressed in epithelial cells, another co-factor, ARA55, was preferentially expressed in stromal cells. Although the changes in levels of these co-activators did not correlate with Gleason score, their occurrence in high-grade prostatic intraepithelial neoplasia, suggests their involvement in initiation (or an early stage) of cancer. In addition, human prostate tumor cell proliferation and colony formation were markedly reduced by ELE1/ATRA70. Together, these findings indicate that changes in levels of expression of AR co-factors may play important, yet different, roles in prostate tumorigenesis
— id: 42676, year: 2002, vol: 161, page: 1467, stat: Journal Article,

Tuberous sclerosis in a 19-week fetus: immunohistochemical and molecular study of hamartin and tuberin
Wei, Jianjun; Li, Peng; Chiriboga, Luis; Mizuguchi, Masashi; Yee, Herman; Miller, Douglas C; Greco, M Alba
2002 Sep-Oct;5(5):448-464, Pediatric & developmental pathology
Tuberous sclerosis complex (TSC) is a genetically heterogeneous disease caused by mutations of TSC1 or TSC2 genes. It involves multiple organ systems resulting in mild to lethal hamartoma formation due to gene mutation in the germ line and loss of heterozygosity (LOH) in somatic cells. Hamartin (TSC1) and tuberin (TSC2) are expressed broadly. However, little is known about tissue susceptibility to hamartomas when equal or similar amounts of TSC gene expression are present. In this study, we present a 19-week gestational age fetus with pathological features of TSC, which was confirmed by finding LOH of TSC2 in a cardiac rhabdomyoma. Developmental expression of hamartin and tuberin in the TSC fetus, an age-matched non-TSC fetus, and a 26-week gestational age non-TSC fetus were analyzed by immunohistochemistry. We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues. In general, hamartin and tuberin are mainly expressed in epithelial cells, myocytes, and neural tissues. By comparing the incidence of the hamartomas in early childhood and gene expression in tissues, it appears that tissues with co-expression of hamartin and tuberin are prone to a higher incidence of hamartomas than those expressing only one protein, or two proteins but in different patterns of cellular localization
— id: 39409, year: 2002, vol: 5, page: 448, stat: Journal Article,

Dynamic three-dimensional MR renography for the measurement of glomerular filtration rate
Lee, VS; Rusinek, H; Lee, P; Kramer, EL; Lavelle, MT; Weinreb, JC
2001 NOV ;221(2):633-634, Radiology
— id: 73269, year: 2001, vol: 221, page: 633, stat: Journal Article,

Inhibition of androgen receptor-mediated transcription by amino-terminal enhancer of split
Yu X; Li P; Roeder RG; Wang Z
2001 Jul;21(14):4614-4625, Molecular & cellular biology
A yeast two-hybrid assay has identified an androgen-dependent interaction of androgen receptor (AR) with amino-terminal enhancer of split (AES), a member of the highly conserved Groucho/TLE family of corepressors. Full-length AR, as well as the N-terminal fragment of AR, showed direct interactions with AES in in vitro protein-protein interaction assays. AES specifically inhibited AR-mediated transcription in a well-defined cell-free transcription system and interacted specifically with the basal transcription factor (TFIIE) in HeLa nuclear extract. These observations implicate AES as a selective repressor of ligand-dependent AR-mediated transcription that acts by directly interacting with AR and by targeting the basal transcription machinery
— id: 42677, year: 2001, vol: 21, page: 4614, stat: Journal Article,

Assessment of activated STAT3 oncogene expression in breast carcinoma
Li, P; Feiner, H; Melamed, J; Linkov, I; Devgan, G; Delgado, Y; Bromberg, J
2000 OCT ;114(4):635-635, American journal of clinical pathology
— id: 54462, year: 2000, vol: 114, page: 635, stat: Journal Article,

Advances in the treatment of basal cell carcinoma: the promise of pharmacologic therapy
Vander Straten, M; Lee, P; Weitzul, S; Cockerell, C J; Tyring, S K
2000 ;16:299-318, Advances in dermatology
— id: 123721, year: 2000, vol: 16, page: 299, stat: Journal Article,

Evidence of latent varicella-zoster virus in rat dorsal root ganglia
Annunziato, P; LaRussa, P; Lee, P; Steinberg, S; Lungu, O; Gershon, A A; Silverstein, S
1998 Nov;178 Suppl 1:S48-S51, Journal of infectious diseases
Latent varicella-zoster virus (VZV) was studied in ganglia of rats that had been inoculated subcutaneously with either a high-passaged wild-type, a low-passaged wild-type, or the vaccine strain of virus using in situ hybridization. Nine of 11 rats injected with virus and no control rats developed serum VZV antibodies as demonstrated by fluorescent antibody membrane antigen. Polymerase chain reaction 2 weeks following inoculation did not detect viremia in the rats. VZV was detected by in situ hybridization in ganglia of 10 of the 11 infected rats but not in ganglia of the control rats. The distribution of VZV DNA is identical to that seen in humans; satellite cells and neurons contain VZV DNA. Although all animals received unilateral injections of virus, VZV DNA was in ipsilateral and contralateral ganglia in 6 animals, suggesting that virus replication and viremia had occurred
— id: 121965, year: 1998, vol: 178 Suppl 1, page: S48, stat: Journal Article,

Characterization of functional regions in the Schizosaccharomyces pombe mei3 developmental activator
Wang W; Li P; Schettino A; Peng Z; McLeod M
1998 Nov;150(3):1007-1018, Genetics
The Schizosaccharomyces pombe mei3(+) gene is expressed only in diploid cells undergoing meiosis. Ectopic expression of mei3(+) in haploid cells causes meiotic catastrophe. Mei3 is an inhibitor of Ran1/Pat1 kinase and contains a nine-amino-acid motif, Mei3-RKDIII, that resembles two regions in the Ste11 substrate for Ran1/Pat1. Substitution of serine for Arg-81 within Mei3-RKDIII transforms the inhibitor into a substrate for Ran1/Pat1. Thus, it is likely that Mei3-RKDIII defines a pseudosubstrate sequence. In this study, we constructed a series of mei3 deletion mutations and assayed each for activity. This analysis indicates that the carboxy-terminal domain of Mei3 is sufficient for function in vivo. Alanine-scanning mutagenesis identifies critical residues within the inhibitory domain. Two mutations, SM1 and SM8, fail to cause meiotic catastrophe. The SM1 mutation contains alterations of amino acid residues in Mei3-RKDIII. Recombinant SM1 protein exhibits reduced ability to inhibit Ran1/Pat1 kinase in vitro and interacts inefficiently with the kinase in a two-hybrid assay. The SM8 protein binds to Ran1/Pat1 in a two-hybrid assay but fails to inhibit Ran1/Pat1 substrate phosphorylation in vitro. These findings provide evidence that Mei3-RKDIII defines a Ran1/Pat1-binding site that is necessary but not sufficient for inhibition of the kinase. Using fusions to green fluorescent protein, the cellular localization of Ran1 and Mei3 was examined in living cells. Ran1 is concentrated in the nucleus. Mei3 is also enriched in the nucleus and, consistent with the genetic and biochemical results, the inhibitory domain of Mei3 is sufficient for nuclear localization
— id: 42672, year: 1998, vol: 150, page: 1007, stat: Journal Article,

Molecular mimicry in development: identification of ste11+ as a substrate and mei3+ as a pseudosubstrate inhibitor of ran1+ kinase
Li P; McLeod M
1996 Nov 29;87(5):869-880, Cell
ran1+ (pat1+) kinase inhibits exit from the mitotic cell cycle and entry into meiosis. Inactivation of ran1+ by mei3+ is sufficient to precipitate the entire meiotic developmental program. Here, we show that the ste11+ transcription factor is a substrate for ran1+ in vitro and that this reaction is directly inhibited by mei3+. Sequence comparison reveals that ste11+ contains two domains homologous to each other and to a domain of mei3+. Mutagenesis studies reveal that the regions of homology contain substrate specificity determinants. These results identify sequences critical for phosphorylation of ste11+ by ran1+ and suggest that mei3+ employs a pseudosubstrate mechanism for its inhibitory function
— id: 42673, year: 1996, vol: 87, page: 869, stat: Journal Article,

Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae
Wei W; Mosteller RD; Sanyal P; Gonzales E; McKinney D; Dasgupta C; Li P; Liu BX; Broek D
1992 Aug 1;89(15):7100-7104, Proceedings of the National Academy of Sciences of the United States of America
The yeast Saccharomyces cerevisiae CDC25 gene encodes a nucleotide-exchange-factor (NEF) that can convert the inactive GDP-bound state of RAS proteins to an active RAS-GTP complex. CDC25 can activate the yeast RAS proteins as well as the human H-ras protein. CDC25 is a member of a family of yeast genes that likely encode NEFs capable of regulating the RAS-related proteins found in yeast. By aligning the amino acid sequence of CDC25-related gene products we found a number of conserved motifs. Using degenerate oligonucleotides that encode these conserved sequences, we have used polymerase chain reactions to amplify fragments of mouse and human cDNAs related to the yeast CDC25 gene. We show that a chimeric molecule, part mouse and part yeast CDC25, can suppress the loss of CDC25 function in the yeast S. cerevisiae
— id: 42674, year: 1992, vol: 89, page: 7100, stat: Journal Article,