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

项目摘要/摘要 BRCA1基因的胚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， 呵呵)。众所周知，环境因素和遗传因素都与BRCA1的癌症病因有关。 承运人。然而，关于影响生物多样性的生物学机制和环境因素的知识 单倍体不足的BRCA1细胞的基因组稳定性仍然缺乏。此外，饮食制剂可以避免 BRCA1携带者的突变与癌症，特别是雌激素受体(ER)阴性癌症的发生 都是未知的。据报道，从BRCA1携带者中获得的单倍体缺陷的BRCA1细胞表现出 对停滞不前的复制的修复不足。我们的初步结果显示，复制缺陷增加， 单倍体不足的BRCA1细胞暴露在新的环境因素下的DNA断裂，这些因素没有 到目前为止，在BRCA1载体细胞中被描述为导致基因组不稳定。此外，我们的初步数据显示， 可减少单倍体缺陷BRCA1 DNA损伤和提高基因组稳定性的新型膳食剂 细胞。该提案将在目标1和目标2中调查环境因素如何导致DNA复制和修复 导致单倍体不足的BRCA1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 单倍体缺乏ER阴性的BRCA1细胞的突变。总而言之，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和 单倍体缺陷BRCA1乳腺上皮细胞的突变。化学预防药物的鉴定，其 避免单倍体不足的BRCA1细胞发生突变和杂合性缺失，对BRCA1来说是极其重要的 承运人。

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.