Inflammatory Proteins Mediate the Causal Association between Sleep Traits and Breast Cancer: A Mendelian Randomization Study

BACKGROUND 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.

OBJECTIVE 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 (IVW) 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.

CONCLUSIONS 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.