Research Interests
Research Summary
I have devoted my research career for over 20 years to elucidating the fundamental mechanisms by which cancers develop. The interests of my lab are directed to elucidating the key mechanisms by which breast cancers arise, with a particular focus on the role of physiological stresses such as hypoxia (lack of oxygen to the tumor), ionizing radiation, angiogenesis (tumor vascularization), inflammatory cytokines and their control, and on identifying genetic and molecular alterations that control the transition of breast cancers from local to metastatic disease. Our research is focused on the development, progression and metastasis of breast cancer, primarily involving post-transcriptional regulation (the regulation of protein synthesis and mRNA stability). Much of our oncology research effort is directed to the molecular and genetic understanding of advanced breast cancers and the development of new treatment strategies for advanced breast cancers. Other major areas of research in my laboratory include the post-transcriptional regulation of inflammation by inflammatory cytokine gene expression, and post-transcriptional regulation of tumor, inflammatory cell and normal cell gene expression by hypoxia and ionizing radiation.
Post-transcriptional regulation of gene expression in breast cancer
The control of mRNA translation and stability are highly regulated processes which are circumvented in cellular transformation. Translational control is an important target for upregulation as a component of malignant transformation of cells. Our research in this area is directed toward understanding how cellular protein synthesis is controlled and altered by hypoxia that often limits tumor growth, how it is altered as a component of tumor invasiveness and metastasis in breast cancer, and how it is regulated by ionizing radiation in normal and transformed cells. Studies are directed to understanding the pathways that control protein synthesis during breast cancer development and progression, during stresses that promote tumor progression such as hypoxia, and during angiogenesis that promotes new blood vessel growth into tumors. Other studies utilize breast tumor biopsies from clinical trials and model systems to determine alterations at the post-transcriptional level and in gene expression profiles, translational gene expression signatures and gene copy number that are associated with invasiveness and metastasis of different types of breast cancers, and the response of tumors to different treatment strategies.
Much of our research effort has focused on a unique understanding of genetic and molecular characteristics of locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) in a multi-ethnic population, and particularly the importance of the Akt/mTOR/4E-BP1 pathway and translational control. We have been conducting a clinical trial and collecting tumor tissue specimens from a multiethnic group of women treated for LABC here in New York and internationally. This research and that in IBC have led to a new understanding of the genetic and molecular nature of LABC and IBC and new treatment strategies. We are examining whether there are specific genetic alterations that are associated with development of LABC and IBC compared to other forms of breast cancer and developing laboratory animal and cell models of LABC and IBC to better understand these diseases and to test new treatment approaches.
Regulation of the inflammatory response by selective degradation of cytokine and proto-oncogene mRNAs, and diseases associated with deregulation.
Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs that are targeted for rapid degradation by the cell. The loss of rapid degradation of these mRNAs can result in a variety of inflammatory cytokine diseases, including septic shock, psoriasis, dermatitis and even oncogenic transformation. Targeted degradation of short-lived inflammatory cytokine and proto-oncogene mRNAs is controlled in a regulated manner by an AU-rich element (ARE) located in the 3'noncoding region, and by several proteins that bind this sequence. We have shown that the ARE binding protein known as AUF1 is a major regulator of inflammatory cytokine and proto-oncogene mRNA stability. By development of a mouse deleted of the AUF1 gene, we have demonstrated that loss of AUF1 activity may play a role in the development of certain cancers including breast cancer, in the development of psoriasis and other chronic inflammatory diseases, and in the ability to attenuate the inflammatory response following microbial infection and exposure to ionizing radiation. We are studying the mechanisms by which degradation of short-lived inflammatory cytokine and proto-oncogene mRNAs is regulated by AUF1, the mechanisms by which physiological stimuli such as infection and ionizing radiation exposure alter the function of AUF1, the complex of proteins that act on the AU-rich element to control degradation and the diseases caused by knockout of these proteins in mouse model systems.