Mre11-Dependent DNA Damage Responses in Breast Cancer Pathogenesis

乳腺癌发病机制中 Mre11 依赖性 DNA 损伤反应

基本信息

批准号：
10064081
负责人：
Gaorav P Gupta
金额：
$ 40.92万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064081
关键词：
ATM Signaling Pathway Alleles Breast Breast Cancer Model Breast Epithelial Cells Cancer Etiology Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Stage Cells Chromosomal Instability Chromosome abnormality Cicatrix Complex DNA Damage DNA Double Strand Break DNA Repair DNA-dependent protein kinase Data Data Set Development Distant Metastasis ERBB2 gene Engineering Estrogens Gene Expression Gene Mutation Genetic Transcription Genomic Instability Genomics Goals Heterogeneity Human Measures Mediating Microscopy Modeling Molecular Profiling Mus Mutate Mutation Oncogene Activation Oncogenes Pathogenesis Pathway interactions Pattern Penetrance Pharmacology Phenotype Predisposition Reporter Reporting Resolution Role TP53 gene Testing Therapeutic Time Transgenic Organisms Transplantation Tumor Suppression base breast tumorigenesis c-myc Genes cancer prevention cancer therapy chemotherapy clinically relevant genome sequencing genomic aberrations in vitro testing inhibitor/antagonist insight malignant breast neoplasm mouse model neoplastic novel strategies overexpression prevent progesterone receptor negative programs prospective replication stress response sensor single-cell RNA sequencing triple-negative invasive breast carcinoma tumor tumorigenesis tumorigenic whole genome

项目摘要

Project Summary Abstract The Mre11-Rad50-Nbs1 complex is a pleiotropic sensor of DNA double strand breaks that promotes ATM signaling, cell cycle checkpoint activation, and DNA repair. We have recently shown that Mre11 is an essential component of the tumor suppressive DNA damage response (DDR) in a murine model of breast cancer. Mre11 pathway deficiency has also been reported in a significant fraction of human triple negative (estrogen/progesterone receptor negative, HER2 non-amplified) breast cancers (TNBC), which are characterized by rampant chromosomal instability and nearly universal inactivation of the p53 pathway. In this project, we will investigate a role for Mre11-mediated tumor suppression in murine models of TNBC initiated by c-Myc overexpression, Rb1 deletion, and/or p53 deficiency. In Aim 1, we will analyze the effect of Mre11 deficiency on cell cycle checkpoint activation in response to oncogene-induced DNA damage. Time lapse microscopy of DNA damage and cell cycle state transitions will be performed in preneoplastic primary mammary epithelial cells. In Aim 2, we will use single cell whole genome sequencing to quantify stochastic chromosomal aberrations that accumulate during oncogene-induced replication stress in primary mammary epithelial cells. The effect of Mre11 and/or p53 deficiency on the chromosomal instability phenotype at different stages of tumorigenesis will be analyzed. In Aim 3, we will engineer Mre11 mutations in a Rb1/p53-deficient murine TNBC model to measure effects on tumor latency. Gene expression and genomic scar signatures associated with Mre11 deficient breast cancers will be determined, and compared to signatures of Brca1 deficiency. A panel of pharmacological DDR pathway inhibitors will be tested to identify targetable synthetic lethal vulnerabilities of Mre11 deficiency. Collectively, this project will provide insight into p53-independent mechanisms of Mre11-mediated tumor suppression, and identify molecular signatures and therapeutic susceptibilities of Mre11 deficient breast cancer.

项目摘要摘要 MRE11-RAD50-NBS1复合物是DNA双链断裂的多效性传感器，可促进ATM 信号传导，细胞周期检查点激活和DNA修复。我们最近表明MRE11是必不可少的在乳腺癌的鼠模型中，肿瘤抑制DNA损伤反应（DDR）的成分。 MRE11 还报道了大量人类三重阴性的途径缺乏症（雌激素/孕激素受体阴性，HER2未扩增）乳腺癌（TNBC），是其特征是p53途径猖ramp的染色体不稳定性和几乎普遍的失活。在这个项目，我们将研究MRE11介导的肿瘤抑制的作用 C-MYC过表达，RB1缺失和/或p53缺陷。在AIM 1中，我们将分析MRE11的效果细胞周期检查点的缺乏响应癌基因诱导的DNA损伤。时间流逝 DNA损伤和细胞循环状态转变的显微镜将在肿瘤主要原发性中进行乳腺上皮细胞。在AIM 2中，我们将使用单细胞全基因组测序来量化随机在癌基因诱导的原发性乳腺复制应力期间积累的染色体畸变上皮细胞。 MRE11和/或p53缺乏对不同的染色体不稳定性表型的影响肿瘤发生阶段将进行分析。在AIM 3中，我们将在RB1/p53缺乏效率中设计MRE11突变鼠TNBC模型测量对肿瘤潜伏期的影响。基因表达和基因组疤痕特征将确定与MRE11缺乏乳腺癌相关的乳腺癌，并与BRCA1的签名相比不足。将测试一系列药理DDR途径抑制剂以识别可靶向合成 MRE11缺乏症的致命脆弱性。总的来说，该项目将提供对p53独立的见解 MRE11介导的肿瘤抑制的机制，并鉴定分子特征和治疗性 MRE11缺乏乳腺癌的敏感性。