It has long been recognized that female hormones, whether endogenous or exogenous, can be risk factors for female cancers. The overall objective of this Program is to better understand the molecular mechanisms for susceptibility to these hormone-associated cancer. In particular, hormone- mediated carcinogenesis can be seen as a multi-step process that may involve genetic regulation of the effectors of hormones, as well as somatic genetic changes subsequent to hormone exposures. This Program has mobilized investigators in pharmacoepidemiology, field epidemiology, genetic epidemiology, endocrinology, pathology, and molecular biology, to bring their talents to bear on this question, examining the relationships among hormone exposures, inherited susceptibility, and the somatic genetic sequelae of these exposures in the etiology of hormone-sensitive female cancers. This Program is composed of three Projects and four Cores. The genetic modification of hormonal exposures in breast and endometrial carcinogenesis will be studied in Projects 1 and 2. Each will use a population-based case-control study design, where hospitalized incident cases of each disease will be compared to a partially shared set of controls who will be selected randomly from the community using random digit dialing. The comparison of these two groups of cases to a group of community controls without the diseases of interest will be used to investigate risk factors for these diseases. A population-based case- control study offers several important advantages over other types of case-control studies, especially by limiting the possibility of selection bias, the major disadvantage of a non-population-based case-control study. Study subjects in both Projects will undergo a common, structured telephone interview. Particular areas of interest will be hormone exposures, family history, and reproduction-associated exposures, especially parity. In addition, cases will have their medical records reviewed as needed to validate information about their cancer. DNA bio- samples will also be collected to measures specific candidate susceptibility genotypes involved in hormone metabolism. The third Project will complement the population-based etiological studies by contributing to knowledge about molecular events associated with reproductive hormonal exposures that later breast cancer susceptibility. This study will have both an animal component and a human component. The animal component will use an established rodent model to develop and evaluate candidate genetic markers that reflect the molecular changes that occur in the breast as a result of parity. Those biomarkers identified as being of potential importance will then be evaluated further in human breast tissue, attempting to understand those parity-associated molecular changes in breast tissue that alter breast cancer susceptibility. The results from the human tissue will be analyzed in conjunction with exposure data obtained using the same questionnaire as that to be administered in Projects 1 and 2. This information will then be used to explore the basic molecular mechanisms that underlie the known epidemiologic associations between hormone-related reproductive events and breast cancers. The information resulting from this transitional study will also be useful in the future development of genetic markers, that can then be evaluated further in studies such as those in Projects 1 and 2. These three Projects will be supported by four Cores: an Administrative Core (responsible for coordination), a Hospital Network Core (responsible for hospital-based activities, including IRB approvals, case ascertainment, medical record abstraction, and specimen collection), a Field Core (responsible for identification of control subjects, recruitment of subjects into the study, questionnaire development, and administration of interviews), and a Data Management and Biostatistics Core (responsible for development and maintenance of a subject tracking system, data entry, data management, and biostatistical analysis). Each of the four Cores will serve all three of the Projects, in such a way as to maximize quality and efficiency simultaneously.
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