Background: In prior observational investigations, it has been demonstrated that the consumption of milk is associated with the incidence of breast cancer (BC). Despite the existence of a two-sample Mendelian randomization (MR) that suggests a causal relationship between milk intake and breast cancer risk, the outcomes still lack a definitive conclusion. This ambiguity may be attributed to variables such as the variety of milk ingested, estrogen levels, the specific type of BC, and potential confounding factors. Therefore, our principal objective is to establish the causal association between the consumption of skimmed milk and full cream milk and the risk of different types of BC through the utilization of two-sample and two-step MR analyses.

Methods: In this study, we analyzed single nucleotide polymorphisms associated with skimmed and full-cream milk consumption in a cohort of 360,806 individuals from European populations through genome-wide association studies. We conducted a two-sample MR analysis using three different methods: inverse variance weighting (IVW) was used as the main analysis, and MR-Egger and Weighted median were used as supplementary analyses to IVW. We also performed sensitivity analysis, which included leave-one-out analysis, Cochran's Q test to detect heterogeneity, and MR-Egger intercept analysis to detect potential biases caused by pleiotropy. We used two-step MR analysis to evaluate potential mediators of associations.

Results: In the two-sample MR analysis, IVW analysis suggests a potential inverse causal relationship between skimmed milk and BC [OR 0.34, 95% CI (0.12-1.00), P = 0.05]. Subgroup analysis revealed that skimmed milk reduces the risk of estrogen receptor-negative (ER-) breast cancer [OR 0.18, 95% CI (0.04-0.90), P = 0.04], but not estrogen receptor-positive (ER+) breast cancer [OR 0.42, 95% CI (0.15-1.22), P = 0.11]. MR Egger reached similar results, that is, skimmed milk reduces the risk of ER- breast cancer [OR 0.006, 95% CI (0.00-0.70), P = 0.04], but not BC [OR 0.16, 95% CI (0.01-4.66), P = 0.30] and ER+ breast cancer [OR 0.50, 95% CI (0.02-12.61), P = 0.65]. Additionally, we found no causal relationship between full cream milk and BC (P > 0.05). In two-step MR analysis, we found evidence for a mediating role of BMI in the relationship between skimmed milk intake and ER-breast cancer risk.

Conclusion: Our findings strengthen the evidence for a protective effect of skimmed milk consumption on ER-breast cancer risk. Further two-step MR analyses suggest that this protective effect may partly result from body mass index (BMI). There is no evidence that full cream milk consumption affects the risk of BC.