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.

项目摘要/摘要 肥胖是乳腺癌的公认危险因素。在DNA中携带突变的肥胖女性 与瘦肉相比，维修酶BRCA1和BRCA2患乳腺癌的风险更大 BRCA突变载体。分子机制解释了乳腺癌在 肥胖的BRCA突变载体尚不清楚。我们发现肥胖与DNA呈正相关 BRCA突变载体的乳房上皮细胞的损害。我们还发现有条件媒体（CM） 肥胖的乳房脂肪组织刺激DNA损伤与活性氧升高 （ROS）在乳房上皮细胞中。此外，对于DNA修复基因的重要性在乳房中被下调 与瘦女性相比，来自肥胖女性的上皮细胞。该提议将检验以下假设 肥胖诱导的乳腺上皮细胞中DNA损伤的升高是由局部脂肪衍生的因子介导的 1）通过ROS的遗传毒性刺激DNA损伤和/或2）降低DNA修复的能力。 此外，携带BRCA突变会因固有缺陷的DNA修复而增强了这种影响 增加肿瘤的渗透率。旨在降低肥胖的疗法可能会减少DNA损伤，并且 因此减轻了肿瘤负担。为了检验这一假设，该提案的第一个目的将确定 脂肪衍生的因素，负责在乳腺上皮细胞中驱动DNA损伤，并将 确定它们是否通过线粒体ROS起作用。第二个目标将决定肥胖是否是 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 降低肥胖是否足以减轻乳腺DNA损伤的肥胖诱导的升高 导致携带BRCA突变的肥胖小鼠的肿瘤渗透率降低。因素的识别 负责在BRCA突变载体中引起DNA损伤和所涉及的分子机制 突出显示对这种高危人群治疗干预的目标 外科干预以外的选择。该项目将在赞助商克里斯蒂博士的实验室进行。 布朗（Brown）是肥胖相关乳腺癌领域的公认专家，并在共同提案师博士的支持下。 刘易斯·坎特利（Lewis Cantley），在细胞代谢和癌症的背景下，PI3K的世界专家，包括BRCA突变 载体。威尔·康奈尔医学院（Weill Cornell Medical College）和附近的洛克菲勒（Rockefeller）的丰富研究环境 癌症遗传学和基因组专业知识可以 在每个角落都可以找到，非常有利于交换将推动该项目前进的想法。