肥胖是一个已经被证明在一般人群中绝经后女性患乳腺癌的危险因素，定义为身体质量指数（BMI）≥ 30。对于携带BRCA1或BRCA2的生殖系突变的女性来说，BMI是否是一个危险因素并不明确，这是由于流行病学研究的一致性研究结果和这个种群中机制研究的缺乏。在这里，我们显示BRCA突变携带者正常乳腺基质中的DNA损伤与BMI和代谢功能紊乱的生物标志物呈正相关。此外，RNA测序显示肥胖相关的变化影响着BRCA突变携带者的乳房脂肪微环境，包括雌激素生物合成的激活，对相邻的乳腺上皮细胞产生影响。在从携带BRCA突变的女性培养的乳腺组织外植物中，我们发现雌激素生物合成的阻断或雌激素受体活性的减少降低DNA损伤。除此之外，肥胖相关因素，包括瘦素和胰岛素，在BRCA杂合子上皮细胞中增加了DNA损伤，而用瘦素中和抗体或PI3K抑制剂干预这些因素的信号通路可以降低DNA损伤。此外，我们发现增加的脂肪组织与BRCA1+/-小鼠乳腺腺体DNA损伤的增加和恶性肿瘤的弥漫性有关。总之，我们的结果提供了机制性证据，支持BMI的升高和BRCA突变携带者发生乳腺癌的相关性。这表明，在这个群体中，保持较低的体重或药理学地针对雌激素或代谢功能可能会降低乳腺癌的风险。

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.