Abstract
INTRODUCTION: Breast cancer (BC) is the most frequent cancer in women, driven by a combination of genetic, environmental, and lifestyle factors. Whether modifiable sleep behaviors causally affect BC risk remains unclear. Aims of the study were to systematically assess the causal impact of sleep-related phenotypes on overall BC and its major subtypes using two-sample mendelian randomization (MR) and to determine whether inflammatory proteins mediate these relationships. METHODS: Inverse variance weighted served as the main analysis, with sensitivity and reverse-MR analyses as supporting checks. Mediation was quantified with a two-step MR design. RESULTS: Morning chronotype significantly reduced the risk of overall BC (OR = 0.936, 95% CI: 0.893-0.980) and luminal A subtype (OR = 0.944, 95% CI: 0.894-0.996). Short sleep duration was associated with decreased risk of overall BC (OR = 0.482, 95% CI: 0.284-0.818) and luminal A subtype (OR = 0.385, 95% CI: 0.194-0.766), whereas long sleep duration increased the risk of triple-negative BC (OR = 9.433, 95% CI: 2.419-36.775) and luminal A subtype (OR = 2.186, 95% CI: 1.111-4.302). Mediation analysis indicated that CXCL11 accounted for 22.4% of the total causal effect of short sleep duration on luminal A BC. CONCLUSION: Morning chronotype confers protection against BC, whereas prolonged sleep duration elevates the risk of triple-negative and luminal A BC. CXCL11 mediates part of the protective effect of short sleep on luminal A BC. These findings provide evidence-based support for BC prevention strategies focusing on sleep optimization.