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

项目总结/摘要 BRCA 1基因的生殖系突变与更高的致癌风险相关。这种高风险是 与增加的突变率和第二个未受影响的BRCA等位基因的丢失（杂合性丢失， 洛）。众所周知，环境和遗传因素都有助于BRCA 1中的癌症病因学 载波然而，关于影响生物学机制和环境因素的知识， 在单倍不足的BRCA 1细胞中仍然缺乏基因组稳定性。此外，避免 突变和癌症，特别是BRCA 1携带者中雌激素受体（ER）阴性癌症的发展 不知道。据报道，从BRCA 1携带者获得的单倍不足BRCA 1细胞表现出 停滞复制的缺陷修复。我们的初步结果表明，增加复制缺陷和上升， 暴露于新环境因素的单倍不足BRCA 1细胞中的DNA断裂， 迄今为止，在BRCA 1载体细胞中描述了引起基因组不稳定性。此外，我们的初步数据显示， 一种新的饮食剂，可以减少DNA损伤，增加单倍不足BRCA 1的基因组稳定性 细胞本计划将在目标1和2中研究环境因素如何引起DNA复制和修复 导致单倍不足BRCA 1乳腺上皮细胞突变和癌细胞发展的缺陷。 在目标3中，这项研究将确定能够预防这些缺陷并减少 在单倍体不足的ER阴性BRCA 1细胞中的突变。总之，本提案中的实验将 检测影响基因组稳定性的毒素和避免缺陷的新化学预防剂， 单倍不足BRCA 1乳腺上皮细胞的突变。化学预防剂的鉴定， 在单倍不足的BRCA 1细胞中避免突变和洛缺失，对于BRCA 1 载波

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.