): Since the isolation of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, studies have been undertaken to evaluate the biologic functions of their protein products, the cellular pathways with which they interact, and the molecular mechanisms by which their loss predisposes to breast and ovarian cancer development. To date, scientific understanding of the function of the BRCA1 protein remains quite limited. In fact, while consistent data suggest functions for BRCA1 related to growth suppression and the maintenance of genome stability, much of the data about the role of this protein remains controversial. Epidemiologic data that could corroborate the findings of mechanistic studies are not presently available. The proposed study is a molecular epidemiologic comparison of cooperating oncogenes and tumor suppressor genes (TSG) activated or inactivated in the breast tumors and pre-malignant breast lesions of BRCA1 mutation carriers and non-carriers. By bringing the tools of molecular biology to clinically based investigation, molecular epidemiology studies, of the kind proposed here, enable indirect evaluation of disease mechanisms. The unifying hypothesis investigated in the proposed project is that genes that control the same pathways as BRCA1 will less frequently be abnormal in the breast tumors of germline BRCA1 mutation carriers than of non-carriers. Genes that function in pathways that are largely independent of BRCA1 will show abnormalities at comparable rates in the tumors of germline BRCA1 mutation carriers and of non-carriers. In the first two specific aims, immunohistochemical assays will be performed on the tumor samples and concurrent pre-malignant lesions of germline BRCA1 mutation carriers and of non-carriers. The applicants will compare the rates of abnormal expression of: 1) cell cycle control genes (cyclin D1, cyclin E, Rb, p53 and p2l); and 2) apoptosis control genes (Bax-alpha, and BCL-2) in the tissues of carriers and non-carriers. In the third specific aim, a statistical model will be constructed to identify the abnormal oncogene and TSG expression pattern that is associated with each group (BRCA1 mutation carriers and non-carriers) and with each of the pre-malignant histologies. The hypotheses of these studies are well integrated into the ongoing work within the project mentor's laboratory and into the research goals of the principal investigator. The proposed studies will be used to corroborate and/or evaluate the clinical significance of findings from more directly mechanistic studies. The proposed studies may also lead to new insights into disease mechanisms. Such insights can be fully evaluated by more directly mechanistic studies. The mechanistic insights inferred from the studies of each type will be employed in the development of rational chemoprevention interventions.
