Targeted therapies to correct genomic instability in Brca1-deficient cells.

项目摘要： 靶向治疗以纠正BRCA 1缺陷细胞中的基因组不稳定性。 BRCA 1或BRCA 2基因突变的个体约占5- 占发达国家乳腺癌的10%。对于携带突变BRCA 1基因的女性， 一生中有近80%的机会患乳腺癌， 患上卵巢癌目前尚无有效的或靶向的分子治疗方法 改变了这种易感性。在缺乏BRCA 1活性的情况下，细胞无法修复 DNA通过同源重组途径（HR）突破。HR提供无错误 修复DNA损伤的机制，但在缺乏有效的HR的情况下，细胞可以修复DNA 通过其他容易出错的路径损坏。使用这些途径可以导致 形成异常和潜在有害的染色体结构， 肿瘤发生事实上，人们普遍认为BRCA 1缺陷细胞不能 执行HR是其在肿瘤形成中的作用的核心。最近的报告表明， 可能通过删除DNA的基因来恢复BRCA 1缺陷细胞中的HR活性 损伤响应因子53 BP 1。这些结果表明，在BRCA 1缺陷细胞中，53 BP 1 可能作为HR的分子抑制剂。此外，抑制53 BP 1活性可能会降低 BRCA 1介导的乳腺癌的发病率。这项拟议中的研究将探讨小说 这意味着有可能在BRCA 1细胞和组织中恢复接近正常的HR活性。 53 BP 1和BRCA 1之间的相互作用将进一步表征，以完善我们的 了解潜在的机制，以及尝试开发先导化合物 抑制53 BP 1功能。对这一现象的更充分理解将导致有针对性的 降低BRCA 1和潜在BRCA 2中肿瘤形成的终生风险的疗法 载波

Project Abstract: Targeted therapies to correct genomic instability in BRCA1-deficient cells. Individuals with mutations in either the BRCA1 or BRCA2 gene account for approximately 5- 10% of all breast cancers in the developed world. For women carrying a mutant BRCA1 gene, there is a nearly 80% lifetime chance of developing breast cancer and a nearly 40% chance of developing ovarian cancer. At present, there are no effective or targeted molecular therapies that modify this susceptibility. In the absence of BRCA1 activity, cells are incapable of repairing DNA breaks through the homologous recombination pathway (HR). HR provides an error free mechanism to repair DNA damage, but in the absence of efficient HR, cells can repair DNA damage though other error-prone pathways. The use of these pathways can lead to the formation of abnormal and potentially harmful chromosomal structures that promote tumorigenesis. Indeed, it is generally believed that the inability of BRCA1 deficient cells to perform HR is central to its role in tumor formation. Recent reports have demonstrated that it is possible to restore HR activity in BRCA1 deficient cells by deletion of the gene for the DNA damage response factor, 53BP1. These results suggest that in BRCA1-deficient cells, 53BP1 may act as a molecular inhibitor of HR. Furthermore, inhibiting 53BP1 activity may reduce the incidence of BRCA1-mediated breast cancer. The proposed research will explore the novel notion that it may be possible to restore near normal HR activity in BRCA1 cells and tissues. The interplay between 53BP1 and BRCA1 will be further characterized to refine our understanding of the underlying mechanism, as well as an attempt to develop lead compounds that inhibit 53BP1 function. A fuller understanding of this phenomenon will lead to targeted therapies to reduce the lifetime risk of tumor formation in BRCA1 and potentially BRCA2 carriers.