The products of the hereditary breast cancer genes BRCA1 and BRCA2 are involved in the repair of DMAdouble-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 distinctcharacteristics, strongly suggesting differences in tumorigenic pathways.
In Specific Aim #1, we will probeaspects of the DNA damage response in mammary epithelium at periods of developmental risk and withoncogenic stress. Mammary gland development is unusual in terms of the cycles of proliferation anddifferentiation that occur after birth and which are greatly modified by pregnancy. Epidemiologic studies inhuman and carcinogen studies in rodents have emphasized the protective effect of pregnancy. In the firstpart of this aim, we test whether parity leads to alterations in aspects of the DNA damage response. In thesecond part of this aim, we systematically explore the activation of the DNA damage response brought aboutby oncogene expression and assess whether defective repair modifies this response. These studies makeuse of transgenic mouse models developed in the last cycle that express dominant-interfering peptides forHDR (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 dnHDRpeptides are expressed in mice following transgene induction.
In Specific Aim #2, we will continue toestablish and analyze cohorts of dnHDR mice and define their tumor histopathology. A major goal is toassess the requirement for continued HDR disruption for tumor progression. We will determine if commonsites of genetic loss/gain can be identified for the different dnHDR peptides. Moreover, we will expand theanalysis of tumors by serial tumor grafting, in order to be able to assess additional genetic changes thatoccur 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 tumordevelopment in the mammary epithelium when HDR is impaired. Angiogenic requirements for tumors arisingfrom HDR defects will be determined. Finally, we will examine the effect of HDR disruption on an establishedoncogene-induced mouse tumor model.
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