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.

项目概要/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 与瘦肉精相比，修复酶 BRCA1 和 BRCA2 患乳腺癌的风险更大 BRCA突变携带者。解释乳腺癌外显率增加的分子机制 肥胖 BRCA 突变携带者尚不清楚。我们发现肥胖与DNA呈正相关 BRCA突变携带者的乳腺上皮细胞受损。我们还发现条件培养基（CM）来自 肥胖乳房脂肪组织会刺激与活性氧升高相关的 DNA 损伤 (ROS) 存在于乳腺上皮细胞中。此外，对 DNA 修复很重要的基因在乳房中下调 肥胖女性与瘦女性的上皮细胞比较。该提案将检验以下假设： 肥胖引起的乳腺上皮细胞 DNA 损伤的增加是由局部脂肪衍生因子介导的 其中 1) 通过 ROS 的基因毒性作用刺激 DNA 损伤和/或 2) 降低 DNA 修复能力。 此外，携带 BRCA 突变会增强这种效应，因为内在缺陷 DNA 修复会导致 肿瘤外显率增加。旨在减少肥胖的疗法可能会减少 DNA 损伤 从而减少肿瘤负荷。为了检验这一假设，该提案的首要目标是确定 脂肪衍生因子负责驱动乳腺上皮细胞 DNA 损伤，并且会 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轻肥胖引起的乳腺 DNA 损伤 导致携带 Brca 突变的肥胖小鼠的肿瘤外显率降低。因素的识别 造成 BRCA 突变携带者 DNA 损伤的原因及其分子机制 强调针对目前接受治疗很少的高危人群的治疗干预目标 手术干预以外的选择。该项目将在赞助商 Kristy 博士的实验室进行 布朗是肥胖相关乳腺癌领域公认的专家，在共同发起人 Dr. Brown 的支持下。 Lewis Cantley，细胞代谢和癌症（包括 BRCA 突变）背景下 PI3K 的世界专家 载体。威尔康奈尔医学院和邻近的洛克菲勒大学拥有丰富的研究环境 大学和纪念斯隆凯特琳癌症中心，癌症遗传学和基因组学专业知识可以 每个角落都可以找到，非常有利于思想交流，从而推动该项目向前发展。