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Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

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Annual rept. 7 Apr 2003-6 Apr 2004

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The hypothesis that depurinating estrogen-DNA adducts initiate breast cancer by generating mutations is at the center of the research in this BCCOE. Inhibition of this adduct formation is anticipated to reduce estrogen-induced mutagenesis, neoplastic transformation and development of tumors. The research includes 1 Testing the ability of two preventative agents to inhibit the induction of mammary tumors in female ACI rats implanted with estradiol. The profile of estrogen metabolites, conjugates, and depurinating DNA adducts and the expression of estrogen-metabolizing enzymes will be analyzed. 2 Determining the effects of estrogen metabolites on neoplastic transformation of human breast epithelial cells and the ability of the preventive agents to block transformation. 3 Preventing estradiol-induced mutations in mammary tissue of Big Blue rats and in cultured cells. 4 Determining the profile of estrogen metabolites, conjugates and DNA adducts in aromatase-transfected mouse mammary tissue and the ability of an aromatase inhibitor to prevent tumors. 5 Studying the role of estrogen in the induction of mammary tumors in female castrate ERKOWnt-1 mice with and without administered estradiol. 6 Studying the profile of metabolites, conjugates, DNA adducts and estrogen-metabolizing enzymes in human breast ductal lavage samples to determine whether analysis of breast fluid might be noninvasive bioassay for risk of breast cancer. 7 Designing a clinical trial of breast cancer prevention in women based on the results of the above studies. The synergism in these studies rests on the complementary, collaborative scientific approaches. Consumer advocates will support this research and disseminate the findings. The results from this Center are expected to provide strategies for preventing human breast cancer and assessing risk of disease.

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  • Medicine and Medical Research

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