BRCA1 and BRCA2: Homology-Directed DNA Repair and Breast Cancer

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The products of the hereditary breast cancer genes BRCA1 and BRCA2 are involved in the repair of DMA double-strand breaks (DSBs) by homologous recombination, termed homology-directed DNA repair (HDR). Although loss of both BRCA1 and BRCA2 predispose to breast cancer, tumors that arise have distinct characteristics, strongly suggesting differences in tumorigenic pathways. In Specific Aim #1, we will probe aspects of the DNA damage response in mammary epithelium at periods of developmental risk and with oncogenic stress. Mammary gland development is unusual in terms of the cycles of proliferation and differentiation that occur after birth and which are greatly modified by pregnancy. Epidemiologic studies in human and carcinogen studies in rodents have emphasized the protective effect of pregnancy. In the first part of this aim, we test whether parity leads to alterations in aspects of the DNA damage response. In the second part of this aim, we systematically explore the activation of the DNA damage response brought about by oncogene expression and assess whether defective repair modifies this response. These studies make use of transgenic mouse models developed in the last cycle that express dominant-interfering peptides for HDR (dnHDR). These dnHDR peptides are mutant forms of Rad51 and peptides that interfere with BRCA2- Rad51 and BRCA1-BARD1 interaction. Mammary tumors have thus far been observed when dnHDR peptides are expressed in mice following transgene induction. In Specific Aim #2, we will continue to establish and analyze cohorts of dnHDR mice and define their tumor histopathology. A major goal is to assess the requirement for continued HDR disruption for tumor progression. We will determine if common sites of genetic loss/gain can be identified for the different dnHDR peptides. Moreover, we will expand the analysis of tumors by serial tumor grafting, in order to be able to assess additional genetic changes that occur with continued growth. The metastatic potential and transcriptional signature will be assessed. In Specific Aim #3, we plan to identify genetic and chemotherapeutic modifiers that delay or promote tumor development in the mammary epithelium when HDR is impaired. Angiogenic requirements for tumors arising from HDR defects will be determined. Finally, we will examine the effect of HDR disruption on an established oncogene-induced mouse tumor model.