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

项目摘要/摘要 肥胖是乳腺癌的一个公认的风险因素。携带DNA突变的肥胖女性 与瘦肉型相比，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 肥胖的BRCA突变携带者尚不清楚。我们发现肥胖与DNA呈正相关 BRCA突变携带者乳腺上皮细胞损伤的研究我们还发现，条件培养液(CM)来自 肥胖的乳房脂肪组织刺激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DNA修复基因在乳房中下调 肥胖女性与瘦女性上皮细胞的比较。这项提议将检验这样一个假设： 肥胖诱导的乳腺上皮细胞DNA损伤的增加是由局部脂肪衍生因子介导的 这1)通过ROS的遗传毒性效应刺激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，因为固有的DNA修复缺陷会导致 肿瘤透过率增加。旨在减少肥胖的治疗方法可能会减少DNA损伤和 从而减轻肿瘤负担。为了检验这一假设，该提案的第一个目标将确定 脂肪衍生因子负责驱动乳腺上皮细胞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 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 减脂是否足以减轻肥胖引起的乳腺DNA损伤 导致携带BRCA突变的肥胖小鼠肿瘤穿透性降低。因素的识别 导致BRCA突变携带者DNA损伤的原因及其所涉及的分子机制 强调对目前很少接受治疗的高危人群进行治疗干预的目标 手术干预以外的选择。该项目将在赞助商克里斯蒂博士的实验室进行。 布朗是肥胖相关乳腺癌领域的公认专家，他得到了共同赞助人Dr。 刘易斯·坎特利，PI3K在细胞代谢和癌症方面的世界专家，包括BRCA突变 承运人。威尔康奈尔医学院和邻近的洛克菲勒丰富的研究环境 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专业知识可以 在每个角落都可以找到，这非常有利于思想的交流，推动这个项目向前发展。

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.