-edited) Breast cancer leads all cancer incidence among American women, accounting for 32 percent of the 1995 estimated new cases in the United States. It is the second leading cause of cancer deaths, estimated at 46,000 per year. Estrogens, natural or synthetic, used widely in a variety of clinical conditions, from estrogen replacement therapy to cancer treatment, are themselves carcinogenic, causing uterine, liver, and breast cancers. However, the mechanism of their carcinogenic action is still not well understood. Because estrogens are required for the growth and development of target cells, it has long been believed that estrogens are promoters for carcinogenesis. Recent studies have demonstrated that estrogens are activated by the microsome P450 enzymes to epoxides which are able to bind DNA, forming estrogen-DNA adducts. These findings suggest the possibility that estrogens may also be initiators for carcinogenesis. Taking advantage of our experience during the past 15 years on aflatoxin B, research and expertise in the applications of microsome activation system, as well as the extremely versatile epoxide-forming oxidant dimethyldioxane to generate epoxides in vitro, we have synthesized the epoxides of the commonly used estrogens: 17-beta- estradiol (E2), estrone, diethylstilbestrol (DES) and tamoxifen (TAM).
The specific aims of this proposal are: (1) to study and compare the binding potentials and specificities of E2, estrone, DES and TAM epoxides on several single- and double-stranded DNAs with known base content and sequence and (2) to study and compare the relative transcriptional effects of these estrogen modified DNA templates on DNA-dependent RNA synthesis. We believe that the results from these studies will not only shed new insights into the mechanism of actions and carcinogenic potentials of these estrogens, but will also help in the future strategic planning for the proper clinical applications of these estrogens.
