Exploiting replication stress at telomeres in triple negative breast cancer

项目摘要 年，大约57,000名美国妇女将死于三重阴性乳腺癌(TNBC)。 2020年。虽然只是所有乳腺癌的一个子集，但它们是高度侵袭性的，并提供最糟糕的 预后。复发率很高，特别是在非裔美国妇女中，到目前为止没有 有针对性的治疗方法是可用的。因此，迫切需要开发新的治疗方案。 尽管进行了大规模的基因组测序工作，但已知的乳腺癌基因座仍然只解释了一个- 乳腺癌风险的三分之一。因此，确定其他乳腺癌是当务之急。 易感基因，并阐明它们的作用机制，使之能够发生 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，它们特定地相互作用 在BRCA1缺失的TNBCs中，端粒结合蛋白TRF2位于功能失调的端粒。这 新的发现为复制体复合体如何赋予 BRCA1空TNBCs的生存优势。对复制体如何保护的新认识 BRCA1缺失的TNBCs中复制的端粒对于新的 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.