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

项目总结 突变的BRCA1和BRCA2 DNA修复酶与乳腺癌和卵巢癌风险增加有因果关系 癌症。最近的证据表明，癌症发生在这些激素敏感部位，至少部分原因是 雌激素的促增殖和致突变作用。我们报告称，肥胖的女性 发炎的乳房脂肪组织中雌激素产生的限速酶--芳香酶的水平。这 可能会导致局部雌激素的产生增加，这可能解释了为什么肥胖后 更年期妇女患激素受体阳性乳腺癌的风险增加。肥胖症有 据报道，BRCA1/2突变携带者会增加乳腺癌的外显率。一个重要的和潜在的 变革性的研究挑战是确定我们对肥胖-炎症-芳香酶的发现 在BRCA1/2突变携带者中，LINK在乳腺癌的发病机制中起重要作用。我们现在可能有场- 不断变化的初步数据表明，获得性特征，如肥胖和脂肪 炎症与乳腺脂肪基质细胞芳香化酶表达增加有关 BRCA突变携带者正常乳腺上皮DNA损伤增加。在这 建议，我们将检验肥胖与乳房白色脂肪组织炎症相关的假说 (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，这将导致乳房上皮细胞的DNA损伤并增加 肿瘤负担。检验这一假说的方法是，首先调查肥胖与肥胖、 BRCA1/2突变中乳房症状和全身因素(如雌激素、胰岛素、瘦素、IL-6)水平的升高 承运人(目标1)。然后，我们将评估体重指数(BMI)、乳房水分、雌激素之间的相关性 和正常乳腺上皮的DNA损伤(目标2)。鉴于雌激素在人体内的重要性， 遗传性乳腺癌的发病机制，接下来我们将描述芳香酶调节的机制。 BRCA突变携带者的乳腺脂肪基质细胞(目标3)。最后，我们将利用鼠标模型来 确定抑制雌激素生物合成是否可以减少乳腺DNA损伤和增加 肿瘤潜伏期，同时也探索生活方式干预，即减少卡路里摄入量，或 药物干预，即使用抗糖尿病药物二甲双胍，可以防止这些促癌作用 改变(目标4)。通过关注雌激素、DNA损伤和乳腺癌之间的潜在联系，这项研究 这项研究承诺为BRCA1/2中肥胖增加乳腺癌外显率的原因提供见解 突变携带者。重要的是，在这一高危人群中的结果可能被证明与理解 散发性乳腺癌肥胖与癌症联系的潜在机制。最后，我们的发现应该是 强化以证据为基础的降低风险战略的理由。

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.