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:10531538
- 负责人:
- 金额:$ 41.37万
- 依托单位:
- 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:
- 关键词:ATM Signaling PathwayAccelerationAllelesApicalBreastBreast Cancer ModelBreast Epithelial CellsCancer EtiologyCell CycleCell Cycle CheckpointCell Cycle ProgressionCell Cycle StageCellsChromosomal InstabilityChromosome abnormalityCicatrixComplexDNA DamageDNA Double Strand BreakDNA RepairDNA-dependent protein kinaseDataData SetDevelopmentDistant MetastasisERBB2 geneEngineeringEstrogensGene ExpressionGene MutationGenetic TranscriptionGenomic InstabilityGenomicsGoalsHeterogeneityHumanMeasuresMediatingMicroscopyModelingMolecular ProfilingMusMutateMutationNeoplasmsOncogene ActivationOncogenesPathogenesisPathway interactionsPatternPenetrancePhenotypePredispositionProliferatingReporterReportingResolutionRoleTP53 geneTestingTherapeuticTimeTransgenic OrganismsTransplantationTumor PromotionTumor Suppressionbreast tumorigenesisc-myc Genescancer initiationcancer preventioncancer therapychemotherapyclinically relevantgenome sequencinggenomic aberrationsin vitro testinginhibitorinsightmalignant breast neoplasmmouse modelneoplasticnovel strategiesoverexpressionpharmacologicpreventprogesterone receptor negativeprogramsprospectivereplication stressresponsesensorsingle-cell RNA sequencingtreatment responsetriple-negative invasive breast carcinomatumortumorigenesistumorigenicwhole 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。
项目成果
期刊论文数量(0)
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Gaorav P Gupta其他文献
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{{ truncateString('Gaorav P Gupta', 18)}}的其他基金
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
- 批准号:
10296655 - 财政年份:2018
- 资助金额:
$ 41.37万 - 项目类别:
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
- 批准号:
10064081 - 财政年份:2018
- 资助金额:
$ 41.37万 - 项目类别:
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