Human and Murine Models of BRCA1 Tumorigenesis

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DESCRIPTION (provided by applicant): BRCA1 is for the cellular to DNA and for reco`mbination, although required response damage homologous it is not yet clear exactly what role it plays in these critical processes. BRCA1 also acts as a co-activator of p53-responsive promoter elements, suggesting that modulating expression of genes that mediate apoptosis and cell cycling is part of this process. Yet, given the universal nature of these cellular processes, it is difficult to explain the striking differences in cancer risk between breast and other tissues in women with BRCA1 germline mutations. The answer will lie in a meticulous dissection of events that initiate and drive BRCAl-associated tumorigenesis. One important clue is that of hormone responsiveness in the tissues at highest risk. During the last funding period, we developed a murine model that recapitulates a known disease-associated human germline BRCA1 mutation with a conditional deletion of the C-terminus of Brca1. We will use that model to ask: What genetic events are necessary for BRCA1-related tumors to develop? The specific aims of this proposal are: Aim 1: To generate murine mammary hyperplasia and carcinomas in mice with a homozygous deletion of the Brcal BRCT domain. Aim 2: To define the early genetic changes in BRCA1 related tumorigenesis using genomic analyses of murine and human tissue Aim3: To define the role of estrogen in the initiation and progression of Brcal-associated mammary tumors. Aim 4: To evaluate the role of haploinsufficiency in BRCA1 mut/wt cells. The completion of this work will define pathways that are altered in BRCAl-associated cancers and will determine whether ER-negative breast cancers predominate in women with BRCA1 mutations because they arise from cells that are intrinsically ER negative or because other proliferative advantages replace ER signaling. We will determine whether heterozygous BRCA1 wt/mut cells have higher mutation rates than BRCA1 wt/wt cells, and whether this effect, if present, is enhanced by estrogen. A complete understanding of these events will lead to testable strategies for prevention, early diagnosis and treatment for women with BRCA1 mutations as well as an enhanced understanding of the molecular events that drive cancer development in general.