多囊卵巢综合症（PCOS）是一种内分泌疾病，以卵巢囊肿、高雄激素水平和月经不调为特征。 PCOS 和乳腺癌 (BC) 之间的因果关系已被广泛讨论，因为它们在临床表现上有显着的交叉点。既往的流行病学研究尚未就 PCOS 与 BC 之间的关联提供一致的结论，而孟德尔随机 (MR) 分析已证实 PCOS 与雌激素受体阳性乳腺癌 (ER  BC) 之间的因果关系，但在 PCOS 引起的一系列临床表现中，哪些相关特征介导因果效应仍然未知。在本研究中，我们进行了多变量孟德尔随机化 (MVMR) 分析，以探索 PCOS 与 BC 不同亚型之间联系机制中的潜在中介变量，并计算中介效应比例。我们分析了13个与PCOS相关的性状，发现绝经年龄可能通过同源重组修复DNA双链断裂介导PCOS诱导的ER  BC（比例为-4.82%），保护作用较弱。这项研究有助于更好地理解导致 PCOS 和 BC 发展的共同机制，并筛查 BC 高危人群并采取适当的预防措施。© 2023。作者。

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovarian cysts, high androgen levels, and irregular menstruation. The causality between PCOS and breast cancer (BC) has been widely discussed as they share a significant intersection in clinical manifestations. Previous epidemiological studies have not provided consistent conclusions in association between PCOS and BC, while mendelian randomization (MR) analyses have confirmed the causality between PCOS and estrogen receptor-positive breast cancer (ER + BC), but among a series of clinical manifestations resulting from PCOS, which related traits mediate the causal effect remains unknown. In this study, we conducted multivariable mendelian randomization (MVMR) analysis to explore the potential mediator variables in the mechanism linking PCOS to distinct subtypes of BC, and calculated the mediating effects proportion. We analyzed 13 PCOS-related traits and found that age at menopause may mediate PCOS-induced ER + BC (with -4.82% proportion) with a weak protective effect through the repair of DNA double-strand breaks by homologous recombination. This study helps to better comprehend the shared mechanisms contributing to the development of both PCOS and BC, and to screen high-risk populations for BC and take appropriate preventive measures.© 2023. The Author(s).