We showed that tumor promoters induce oxidants and DNA base oxidation in cultured and epidermal cells isolated from mice treated in vivo. Anti-tumor promoters inhibited the tumor promoter mediated inflammation, edema, neutrophil infiltration, and formation of H2O2 and of oxidized DNA bases [5-hydroxy-methyl-2'-deoxyuridine (HMdU) and 8-hydroxy-2'-deoxyguanosine (8-OHdG)]. These anti-promoters included (-) epi-gallocatechin gallate (EGCG, from green tea), caffeic acid phenethyl ester (CAPE, the propolis of honeybee hives), sarcophytol A (soft coral), and Tamoxifen (TAM, an anticancer drug). 7,12-Dimethylbenz[a]anthracene (DMBA), a complete carcinogen, also causes neutrophil infiltration, H2O2, HMdU, and 8-OHdG formation in the skin of topically treated mice. Hence, inflammation with its attendant oxidative stress and oxidative DNA base modification may be common denominators of tumor promotional processes. Therefore, inhibiting those processes with antioxidants and other chemopreventive agents might protect against cancer development. We find that DMBA induces the formation of an inflammatory cytokine IL-1a in mouse skin akin to tumor promoter TPA. IL-1a initially works to counteract the initiation step but, once tumors are formed, it contributes to the tumor promotion and progression to carcinomas in DMBA-treated mouse skin. More recently, we have been studying the mechanism of human cell transformation by arsenite or by estradiol and searching for agents that can prevent cell transformation and/or kill the already transformed cells. We find that CAPE (see above), even when used at very low doses, can prevent As-induced human cell transformation and counteract massive down-regulation of inflammatory cytokines and of the transcription factor NF-kB1, as well as induce apoptosis in As-transformed cells or cancerous breast epithelial cells, without any effect on normal cells. Genes and their protein products involved in the cell transformation are being determined. Currently, we are using a nude mouse model to establish the effects of CAPE on the growth of human breast cancer cells as xenografts. We find that CAPE inhibits growth of breast cancer ER(+) as well as ER(-) cells as tumors at doses that are very low (nmol amounts of CAPE/-mouse/day). CAPE causes down-regulation of cell proliferation, pro-survival, and cell cycle-related genes, growth factors, oncogenes, inflammatory cytokines and chemokines, pro-angiogenic factors and certain transcriotion factors. All these properties might be useful in inhibiting growth, angiogenesis, and possibly recurrance of breast cancer in patients. In addition, we discovered that people elaborate autoantibodies (aAb) recognizing HMdU when it is coupled to bovine serum albumin. Anti-HMdU aAb titers are significantly elevated in the sera of women with a family history of cancer and those who may develop cancer (breast or colorectal). People occupationally exposed to carcinogenic metals also exhibit elevated anti-HMdU aAb titers, which could be used to identify people at risk for developing cancer. In summary, our investigations are focused on: 1) studies on the mechanisms of cell transformation and carcinogenesis, with the emphasis on the role of inflammatory factors; 2) establishing whether EGCG, CAPE, and TAM suppress DMBA-mediated carcinogenesis; 3) elucidating mechanism(s) by which EGCG, CAPE, and TAM exert their protective action; 4) conducting molecular epidemiology studies to prove that anti-HMdU aAb can provide a measure of cancer risk; and 5) evaluating whether CAPE could have clinical applications in preventing and/or treating human breast cancer.