Mechanisms of obesity-induced breast epithelial cell DNA damage in BRCA mutation carriers

BRCA突变携带者肥胖引起乳腺上皮细胞DNA损伤的机制

• 批准号: 10164734
• 负责人: Priya Bhardwaj
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164734
• 关键词: Adipose tissue; Antioxidants; Attenuated; Automobile Driving; BRCA mutations; BRCA1 gene; BRCA2 gene; Behavior Therapy; Behavioral; Biological; Biological Assay; Body mass index; Breast; Breast Cancer Model; Breast Cancer Risk Factor; Breast Epithelial Cells; Caloric Restriction; Cell Line; Cellular Metabolic Process; Complement; Complex; DNA Damage; DNA Double Strand Break; DNA Markers; DNA Repair; DNA Repair Enzymes; DNA Repair Gene; Data; Defect; Development; Environment; Estrogens; Event; Exposure to; Genes; High Fat Diet; Immunofluorescence Immunologic; Impairment; Inflammatory; Intervention; Ionizing radiation; Laboratories; Lead; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Memorial Sloan-Kettering Cancer Center; Mitochondria; Molecular; Mouse Mammary Tumor Virus; Mus; Mutant Strains Mice; Mutation; NBS1 gene; Obese Mice; Obesity; Operative Surgical Procedures; Organoids; Oxidative Stress; Penetrance; Pharmacologic Substance; Pharmacology; Populations at Risk; Production; Reactive Oxygen Species; Research; Risk; Risk Factors; Risk Reduction; Role; Stains; Superoxides; Techniques; Testing; Therapeutic Intervention; Thinness; Time; Tissue Microarray; Tissues; Tumor Burden; Universities; Woman; cancer genetics; cancer genomics; cytokine; diet-induced obesity; genotoxicity; high risk population; inhibitor/antagonist; irradiation; malignant breast neoplasm; mammary epithelium; medical schools; mouse model; mutant; mutation carrier; novel; paracrine; protein expression; targeted treatment; transcriptome sequencing; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Obesity is a well-established risk factor for breast cancer. Obese women who carry a mutation in the DNA repair enzymes BRCA1 and BRCA2 are at a greater risk of developing breast cancer compared with lean BRCA mutation carriers. Molecular mechanisms that explain the increased penetrance of breast cancer in obese BRCA mutation carriers are unknown. We have found that obesity is positively associated with DNA damage in breast epithelial cells of BRCA mutation carriers. We also found that conditioned media (CM) from obese breast adipose tissue stimulates DNA damage in association with elevated reactive oxygen species (ROS) in breast epithelial cells. Furthermore, important for DNA repair genes are downregulated in breast epithelial cells from obese women compared with lean women. This proposal will test the hypothesis that elevation in obesity-induced DNA damage in breast epithelial cells is mediated by local adipose-derived factors which 1) stimulate DNA damage via genotoxic effects of ROS and/or 2) reduce capacity for DNA repair. Furthermore, carrying a BRCA mutation enhances this effect due to intrinsic defective DNA repair leading to increased tumor penetrance. Therapies aimed at reducing adiposity may decrease DNA damage and consequently decrease tumor burden. To test this hypothesis, the first aim of this proposal will identify the adipose-derived factors that are responsible for driving DNA damage in breast epithelial cells and will determine whether they act through mitochondrial ROS. The second aim will determine whether obesity is associated with a defect in DNA repair. Finally, in the third aim, caloric restriction will be utilized to determine whether reducing adiposity is sufficient to attenuate obesity-induced elevation in mammary gland DNA damage leading to decreased tumor penetrance in obese mice carrying a Brca mutation. The identification of factors responsible for causing DNA damage in BRCA mutation carriers and the molecular mechanisms involved will highlight targets for therapeutic intervention in this at-risk population who are currently given few treatment options beyond surgical intervention. This project will be undertaken in the laboratory of sponsor Dr. Kristy Brown, a recognized expert in the field of obesity-related breast cancer, with the support of co-sponsor Dr. Lewis Cantley, world expert in PI3K in the context of cell metabolism and cancer, including in BRCA mutation carriers. The rich research environment at Weill Cornell Medical College and neighboring Rockefeller University and Memorial Sloan Kettering Cancer Center, where cancer genetics and genomics expertise can be found at every corner, is highly conducive to the exchange of ideas that will push this project forward.

项目总结/摘要 肥胖是乳腺癌的一个公认的危险因素。携带DNA突变的肥胖女性 修复酶BRCA 1和BRCA 2与瘦的相比，患乳腺癌的风险更大。 BRCA突变携带者。乳腺癌发病率增加的分子机制 肥胖的BRCA突变携带者是未知的。我们发现肥胖与DNA BRCA突变携带者的乳腺上皮细胞损伤。我们还发现，条件培养基（CM）从 肥胖乳腺脂肪组织刺激DNA损伤与活性氧升高相关 (ROS)在乳腺上皮细胞中。此外，重要的是DNA修复基因在乳腺癌中下调， 肥胖女性和瘦女性的上皮细胞比较。这一提议将检验以下假设： 局部脂肪源性因子介导的乳腺上皮细胞中肥胖诱导的DNA损伤升高 其1）通过ROS的遗传毒性作用刺激DNA损伤和/或2）降低DNA修复能力。 此外，携带BRCA突变增强了这种效应，因为内在缺陷的DNA修复导致 肿瘤转移率增加。旨在减少肥胖的治疗可以减少DNA损伤， 从而降低肿瘤负荷。为了验证这一假设，本提案的第一个目标将确定 脂肪源性因子，负责驱动乳腺上皮细胞的DNA损伤， 确定它们是否通过线粒体ROS起作用。第二个目标将确定肥胖是否是 与DNA修复缺陷有关最后，在第三个目标中，将利用热量限制来确定 减少肥胖是否足以减弱肥胖引起的乳腺DNA损伤 导致携带Brca突变的肥胖小鼠的肿瘤转移率降低。确定因素 BRCA基因突变携带者的DNA损伤的分子机制， 强调目前很少接受治疗高危人群的治疗干预目标 手术干预之外的选择本项目将在申办者Kristy博士的实验室进行 布朗博士是肥胖相关乳腺癌领域公认的专家，他在共同发起人布朗博士的支持下， 刘易斯坎特利，PI 3 K在细胞代谢和癌症背景下的世界专家，包括BRCA突变 载波威尔康奈尔医学院和邻近的洛克菲勒大学丰富的研究环境 大学和纪念斯隆凯特琳癌症中心，在那里癌症遗传学和基因组学的专业知识， 在每一个角落都能找到，这非常有利于交流想法，推动这个项目向前发展。