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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：
10296655
负责人：
Gaorav P Gupta
金额：
$ 42.21万
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/10296655
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 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 Mre 11-BclRad 50-BclNbs 1复合物是DNA双链断裂的多效性传感器，其促进ATM 我们最近的研究表明，Mre 11是一个重要的信号传导，细胞周期检查点激活和DNA修复。 Mre 11是乳腺癌小鼠模型中肿瘤抑制性DNA损伤反应（DDR）的组成部分。在人类三阴性细胞中，（雌激素/孕激素受体阴性，HER 2非扩增）乳腺癌（TNBC），其是其特征在于猖獗的染色体不稳定性和几乎普遍的p53通路失活。项目中，我们将研究Mre 11-β介导的肿瘤抑制在TNBC小鼠模型中的作用，在目的1中，我们将分析Mre 11对c-myc过表达、Rb 1缺失和/或p53缺陷的影响。缺乏细胞周期检查点激活对癌基因-β诱导的DNA损伤的反应。时间间隔将在肿瘤前原发性肝癌中进行DNA损伤和细胞周期状态转换的显微镜检查。在目标2中，我们将使用单细胞全基因组测序来定量随机的乳腺上皮细胞。在原发性乳腺癌中癌基因诱导的复制应激过程中积累的染色体畸变 Mre 11和/或p53缺陷对不同细胞周期的染色体不稳定性表型的影响在目标3中，我们将在Rb 1/p53-p53缺陷的肿瘤细胞中设计Mre 11突变，用于测量对肿瘤潜伏期的影响的鼠TNBC模型。基因表达和基因组瘢痕特征将确定与Mre 11缺陷乳腺癌相关的基因，并与Brca 1 将测试一组药理学DDR途径抑制剂以鉴定靶向合成的 Mre 11缺陷的致命弱点。总的来说，这个项目将提供对p53-p53独立的深入了解。 Mre 11-E2介导的肿瘤抑制机制，并确定分子特征和治疗 Mre 11缺陷型乳腺癌的易感性。