): It is clear that estrogen exposure plays an important role in the etiology of breast cancer. However, in addition to the well-characterized and well-accepted role of estrogen receptor-dependent events in the pathophysiology of breast cancer, a parallel and complementary hypothesis has developed in support of direct estrogen-mediated genotoxicity after the """"""""metabolic activation"""""""" of estrogens to form catecholestrogens (CEs). Many of the enzymes which are involved in estrogen and CE formation, in their metabolic activation to form genotoxins and in their enzymatic inactivation to prevent genotoxicity display common, functionally significant genetic polymorphisms. Therefore, one possible mechanism for the effects of """"""""predisposing genes"""""""" in the pathophysiology of breast cancer would result from the effects of common genetic polymorphisms involving enzymes that catalyze the activation of estrogens and CEs to form genotoxins or the enzymatic inactivation of those genotoxins. We propose to take advantage of the unusual resource represented by the 426 families that we have identified through probands diagnosed with breast cancer to systematically test the hypothesis that common genetic polymorphisms for enzymes that catalyze pathways of estrogen and CE formation, CE metabolic activation to form genotoxins or the metabolic inactivation of those genotoxins might represent """"""""predisposing"""""""" genetic risk factors that can partially explain the familial clustering of breast cancer beyond mutations within the BRCA1 and BRCA2 genes. Specifically, allele frequencies for common genetic polymorphisms of enzymes, predominantly cytochromes P450, that are involved in pathways of estrogen formation and metabolic activation as well as enzymes involved in estrogen and CE metabolism and inactivation (e.g., methylation, sulfation and glutathione conjugation) will be determined in 434 breast cancer cases and 868 control subjects to determine whether genetic polymorphisms for enzymes that catalyze estrogen metabolic bioactivation and/or inactivation might represent inherited risk factors for the occurrence of this common neoplastic disease.
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