Environmental factors and compounds affecting the genomic stability in haploinsufficient BRCA1 cells.

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PROJECT SUMMARY/ABSTRACT Germline mutations in the BRCA1 gene are associated with higher risk of carcinogenesis. This high risk is linked to an increased mutation rate and loss of the second unaffected BRCA allele (loss of heterozygosity, LOH). It is well accepted that both environmental and genetic factors contribute to cancer etiology in BRCA1 carriers. However, knowledge about the biological mechanisms and environmental factors that influence the genomic stability in haploinsufficient BRCA1 cells is still lacking. In addition, dietary agents that avert mutagenesis and cancer, in particular estrogen receptor (ER)-negative cancer development in BRCA1 carriers are not known. It was reported that haploinsufficient BRCA1 cells obtained from BRCA1 carriers exhibit deficient repair of stalled replication. Our preliminary results show an increase replication defects and a rise in DNA breaks in haploinsufficient BRCA1 cells exposed to novel environmental factors, which were not described so far to cause genomic instability, in BRCA1 carrier cells. In addition, our preliminary data reveal a new dietary agent that can reduce DNA damage and increase the genomic stability in haploinsufficient BRCA1 cells. This proposal will investigate in aim 1 and 2 how environmental factors cause DNA replication and repair defects that lead to mutations and cancer cell development in haploinsufficient BRCA1 breast epithelial cells. And in aim 3 this study will identify novel dietary agents that are able to prevent these defects and reduce mutagenesis in haploinsufficient ER-negative BRCA1 cells. In summary, the experiments in this proposal will detect toxins that affect the genomic stability and new chemopreventive agents that avert defects and mutagenesis in haploinsufficient BRCA1 breast epithelial cells. Identification of chemopreventive agents, which avoid mutagenesis and LOH in haploinsufficient BRCA1 cells, would be extremely important for BRCA1 carriers.