Exploiting replication stress at telomeres in triple negative breast cancer

项目摘要 大约57，000名美国妇女将死于三阴性乳腺癌（TNBC）。 2020.虽然它们只是所有乳腺癌的一个子集，但它们具有高度侵袭性，并且是最严重的 预后复发率很高，特别是在非洲裔美国妇女中，迄今为止， 靶向治疗是可用的。因此，迫切需要开发新的治疗方案。 尽管大规模的基因组测序工作，已知的乳腺癌基因座仍然只能解释一个- 三分之一的乳腺癌风险。因此，必须确定其他乳腺癌 易感基因，并阐明其作用机制，使发展 全面的癌症风险评估和靶向治疗。我们最近发现， Claspin、PCNA和DONSON是DNA复制机制的组成部分， 与端粒结合蛋白TRF 2在BRCA 1缺失的TNBC中的功能失调的端粒。这 新的发现提供了新的见解，机制如何复制体复合物赋予 与BRCA 1缺失TNBC相比具有生存优势。了解复制体如何保护新的 BRCA 1缺失TNBC中的复制端粒对于产生新的肿瘤细胞将是非常有价值的。 治疗这种致命疾病的方法

Project Summary Approximately 57,000 American women will succumb to triple negative breast cancer (TNBC) in 2020. While only a subset of all breast cancers, they are highly aggressive and offer the worst prognosis. Recurrence rate is high, especially in African-American women, and to date no targeted therapies are available. There is thus an urgent need to develop new treatment options. Despite large-scale genome sequencing efforts, known breast cancer loci still explain only one- third of breast cancer risk. It is therefore imperative to identify additional breast cancer susceptibility genes and elucidate their mechanisms of action to enable the development of comprehensive cancer risk assessment and targeted therapeutics. We recent discovered that Claspin, PCNA and DONSON, components of the DNA replication machinery, specifically interact with the telomere binding protein TRF2 at dysfunctional telomeres in BRCA1 null TNBCs. This novel discovery provides new insights into mechanisms of how the replisome complex confers a survival advantage to BRCA1 null TNBCs. Understanding how the replisome protects newly replicated telomeres in BRCA1 null TNBCs will be highly valuable for the generation of new therapeutics against this deadly disease.