Genotoxicity of Estrogen Compounds in Endocrine Therapy

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DESCRIPTION (provided by applicant): Estrogen replacement therapy (ERT) is widely used to decrease symptoms associated with menopause and to protect women against osteoporosis. ERT, composed of estrogens, equilin, and equilenin, is associated with increased risk of breast, ovarian, and endometrial cancers. As the major metabolites of estrogen and equine estrogen generate oxidative DNA damage and, in some cases react with DNA to form covalent adducts, it is possible that DNA damage plays a central role in the initiation of estrogen-associated cancers. The proposed studies are designed to determine the level of covalent DNA adducts and oxidative damage generated in mammary and reproductive tissues of rats treated with equine estrogens or their metabolites, as well as establish the mutagenic and repair potential of equine estrogen-derived DNA adducts. Leukocytes and endometrial tissue will be collected from women receiving ERT and analyzed for DNA adducts using ultrasensitive 32P-postlabeling and HPLC/electrochemical detection techniques developed in our laboratory. If such adducts are not fully repaired, DNA lesions will persist in target tissues where they may initiate breast, ovarian, and/or endometrial cancer. By demonstrating that certain components of ERT are genotoxic and by defining the biochemical mechanism involved, it should be possible to design drugs that retain desirable therapeutic properties of ERT but lack its carcinogenic effects. This research will also provide biomarkers that can be used to identify subgroups of women at high risk of developing ERT-induced cancer.