Obesity Increases Breast Cancer Penetrance in BRCA Mutation Carriers: A Role for Local and Systemic Factors

肥胖会增加 BRCA 突变携带者的乳腺癌外显率：局部和全身因素的作用

• 批准号: 9903246
• 负责人: Kristy A. Brown
• 金额: $ 50.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903246
• 关键词: Adipose tissue; Anabolism; Animal Model; Antidiabetic Drugs; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Behavior Therapy; Biological Markers; Blood; Body Weight decreased; Body mass index; Breast; Breast Cancer Model; Breast Cancer Risk Factor; Caloric Restriction; Calories; Characteristics; Common Neoplasm; DNA Damage; DNA Repair Enzymes; Data; Development; Diet; Duct (organ) structure; Energy Intake; Enzymes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Estrogens; Experimental Models; Gene Silencing; Glucose; Hereditary Breast Carcinoma; Hormones; Human Milk; Immunofluorescence Immunologic; Inflammation; Inherited; Insulin; Intake; Interleukin-6; Intervention; Laboratories; Lead; Leptin; Letrozole; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Measures; Metformin; Modeling; Mutant Strains Mice; Mutation; Obesity; Ovariectomy; Pathogenesis; Patients; Penetrance; Pharmacology; Postmenopause; Predisposition; Production; Proteins; Regulation; Reporting; Research; Risk; Risk Reduction; Role; Severities; Signal Pathway; Site; Stromal Cells; Techniques; Testing; Tissues; Tumor Burden; Weight; Western Blotting; Woman; adipokines; evidence base; high risk population; hormone receptor-positive; inflammatory marker; insight; insulin signaling; lifestyle intervention; malignant breast neoplasm; mammary epithelium; mouse model; mutant; mutation carrier; prevent; prophylactic mastectomy; standard of care; tumor; tumorigenesis

PROJECT SUMMARY Mutant BRCA1 and BRCA2 DNA repair enzymes are causally linked to an increased risk of breast and ovarian cancers. Recent evidence suggests that cancers occur at these hormone-sensitive sites, at least in part, due to the pro-proliferative and mutagenic effects of estrogens. We reported that women who are obese have elevated levels of aromatase, the rate-limiting enzyme for estrogen production, in inflamed breast adipose tissue. This would be predicted to lead to increased local production of estrogen and may explain why obese post- menopausal women are at increased risk of developing hormone receptor-positive breast cancer. Obesity has been reported to increase the penetrance of breast cancer in BRCA1/2 mutation carriers. A major and potentially transformative research challenge is determining whether our discovery of the obesity-inflammation-aromatase link is important in the pathogenesis of breast cancer in BRCA1/2 mutation carriers. We now have possibly field- changing preliminary data which suggest that acquired characteristics, such as obesity and adipose inflammation, are associated with increased expression of aromatase in breast adipose stromal cells (ASCs) and an associated increase in DNA damage in the normal breast epithelium of BRCA mutation carriers. In this proposal, we will test the hypothesis that obesity, and associated breast white adipose tissue inflammation (WATi), will increase breast cancer penetrance in BRCA mutation carriers via local and systemic effects, including higher estrogen and insulin levels, that will lead to DNA damage in the breast epithelium and increase tumor burden. This hypothesis will be tested by first investigating whether an association exists between obesity, breast WATi and increased levels of systemic factors (e.g., estrogens, insulin, leptin, IL-6) in BRCA1/2 mutation carriers (Aim 1). Then, we will assess correlations between body mass index (BMI), breast WATi, estrogens and DNA damage in normal appearing breast epithelium (Aim 2). Given the importance of estrogens in the pathogenesis of hereditary breast cancer, we will next characterize mechanisms of aromatase regulation in breast adipose stromal cells of BRCA mutation carriers (Aim 3). Finally, we will utilize mouse models to determine whether suppressing estrogen biosynthesis can reduce mammary gland DNA damage and increase tumor latency, while also exploring whether a lifestyle intervention, i.e. reduction in caloric intake, or pharmacological intervention, i.e. use of the anti-diabetic drug metformin, can prevent these cancer-promoting changes (Aim 4). By focusing on the potential link between estrogen, DNA damage and breast cancer, this study promises to provide insights into why obesity increases the penetrance of breast cancer in BRCA1/2 mutation carriers. Importantly, results in this high risk population could prove relevant for understanding the mechanisms underlying the obesity-cancer connection for sporadic breast cancer. Finally, our findings should strengthen the rationale for evidence-based risk reduction strategies.

项目概要 突变的 BRCA1 和 BRCA2 DNA 修复酶与乳腺癌和卵巢癌风险增加存在因果关系 癌症。最近的证据表明，癌症发生在这些激素敏感部位，至少部分是由于 雌激素的促增殖和诱变作用。我们报道称，肥胖女性的体重升高 发炎的乳房脂肪组织中芳香酶的水平，芳香酶是雌激素产生的限速酶。这 预计会导致局部雌激素产量增加，并可能解释为什么肥胖后 更年期妇女患激素受体阳性乳腺癌的风险增加。肥胖有 据报道，可增加 BRCA1/2 突变携带者的乳腺癌外显率。一个主要的和潜在的 变革性研究的挑战是确定我们是否发现了肥胖炎症芳香酶 这种联系在 BRCA1/2 突变携带者乳腺癌的发病机制中很重要。我们现在可能有领域- 改变初步数据表明获得性特征，例如肥胖和脂肪 炎症，与乳腺脂肪基质细胞 (ASC) 中芳香酶表达增加有关 BRCA 突变携带者正常乳腺上皮的 DNA 损伤也会相应增加。在这个 建议，我们将检验肥胖和相关乳房白色脂肪组织炎症的假设 (WATi)，将通过局部和全身效应增加 BRCA 突变携带者的乳腺癌外显率， 包括较高的雌激素和胰岛素水平，这将导致乳腺上皮细胞 DNA 损伤并增加 肿瘤负荷。该假设将通过首先调查肥胖之间是否存在关联来检验， BRCA1/2 突变导致乳房 WATi 和全身因素（例如雌激素、胰岛素、瘦素、IL-6）水平升高 运营商（目标 1）。然后，我们将评估体重指数 (BMI)、乳房 WATi、雌激素之间的相关性 正常乳腺上皮细胞的 DNA 损伤（目标 2）。鉴于雌激素在身体中的重要性 遗传性乳腺癌的发病机制，接下来我们将描述芳香酶调节机制 BRCA 突变携带者的乳腺脂肪基质细胞（目标 3）。最后，我们将利用小鼠模型 确定抑制雌激素生物合成是否可以减少乳腺 DNA 损伤并增加 肿瘤潜伏期，同时还探索生活方式干预，即减少热量摄入，或 药物干预，即使用抗糖尿病药物二甲双胍，可以预防这些促癌因素 变化（目标 4）。通过关注雌激素、DNA 损伤和乳腺癌之间的潜在联系， 研究有望揭示为什么肥胖会增加 BRCA1/2 乳腺癌的外显率 突变携带者。重要的是，这一高风险人群的结果可能有助于理解 散发性乳腺癌肥胖与癌症关联的潜在机制。最后，我们的发现应该 强化基于证据的风险降低策略的基本原理。