DNA Methylation in RARβ Gene as a Mediator of the Association Between Healthy Lifestyle and Breast Cancer: A Case-Control Study

Purpose: Lifestyle factors and methylation in the retinoic acid receptor beta (RAR beta) gene are associated with breast cancer (BC). This study aims to examine the mediation effect of RAR beta methylation on the association between healthy lifestyle and BC in Chinese women. Patients and Methods: This case-control study consisted of 408 BC patients and 573 controls. A healthy lifestyle score (HLS) was constructed based on diet, alcohol use, physical activity, body mass index and smoking. The mediation effect of RAR beta methylation in peripheral blood leukocytes was assessed in a causal mediation model using R package Lavaan. Results: A higher HLS was significantly associated with lower risk of BC (P-value<0.001). In mediation analyses, the total effect of HLS on BC measured as a regression coefficient was significant (-0.237). The indirect effects of HLS on RAR beta methylation (-0.153) and RAR beta methylation on BC (0.220) were both significant. The significant mediation effect of RAR beta methylation on the HLS-BC association was estimated at 14.3%. Conclusion: The relationship between healthy lifestyle and BC is partly mediated by RAR beta methylation, suggesting that epigenetic modifications play a role in the underlying mechanisms in response to lifestyles and contribute to the development of BC.