Exploiting replication stress at telomeres in triple negative breast cancer

利用三阴性乳腺癌端粒的复制应激

基本信息

批准号：
10046540
负责人：
Sandy S Chang
金额：
$ 16.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-13 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046540
关键词：
Affect African American American Attenuated BRCA1 gene BRCA2 gene Breast Cancer Cell Breast Cancer Model Breast Cancer Risk Factor CHEK1 gene Cancer-Predisposing Gene Cell Line Cells Chromosomes Complex DNA DNA Damage DNA Repair DNA Repair Pathway DNA analysis DNA biosynthesis DNA replication fork Development Disease Engineering Fatty acid glycerol esters Generations Genome Genomic Instability Harvest Human Hypersensitivity Image Immunodeficient Mouse Incubated Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Molecular Monitor Mouse Mammary Tumor Virus NOD/SCID mouse Play Proliferating Cell Nuclear Antigen Property Proteins Recurrence Risk Assessment Role Signal Transduction Techniques Telomere-Binding Proteins Telomeric Repeat Binding Protein 2 Testing Therapeutic Woman Xenograft Model breast cancer progression breast cancer survival cancer risk drinking water genome sequencing genome-wide homologous recombination inhibitor/antagonist insight malignant breast neoplasm mouse model neoplastic cell novel novel therapeutics outcome forecast prevent recruit replication stress response single molecule small hairpin RNA targeted treatment telomere triple-negative invasive breast carcinoma tumor tumor growth tumor progression vector control

项目摘要

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.

项目概要大约 57,000 名美国女性将死于三阴性乳腺癌 (TNBC) 2020 年。虽然只是所有乳腺癌的一小部分，但它们具有高度侵袭性，并且带来最严重的后果预后。复发率很高，尤其是非裔美国女性，迄今为止还没有可以采用靶向治疗。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，已知的乳腺癌基因座仍然只能解释一种情况：乳腺癌风险的三分之一。因此，有必要识别更多的乳腺癌易感基因并阐明其作用机制，以实现全面的癌症风险评估和针对性治疗。我们最近发现 Claspin、PCNA 和 DONSON，DNA 复制机器的组成部分，专门相互作用 BRCA1 无效 TNBC 中功能失调的端粒上有端粒结合蛋白 TRF2。这新的发现为复制体复合物如何赋予复制体的机制提供了新的见解 BRCA1 缺失 TNBC 的生存优势。了解复制体如何保护新的 BRCA1 缺失 TNBC 中的复制端粒对于新一代 TNBC 的产生非常有价值针对这种致命疾病的治疗方法。