DNA Methylation, Physical Activity and Breast Cancer: The Western New York Exposures and Breast Cancer (WEB) Study

Objective: Global and gene-specific DNA methylation play an important role in breast carcinogenesis. However, the influence of lifestyle factors on DNA methylation is unknown. We examined the association between lifetime physical activity (PA) and DNA methylation of E-Cadherin, p16 and RAR-2β genes individually and collectively (≥1 genes). Methods: We used data from the population-based Western New York Exposures and Breast cancer (WEB) case-control study. The WEB study recruited 1,170 women with primary, histologically confirmed breast cancer between 1996 and 2001 in Erie and Niagara counties of New York State. Lifetime PA was estimated using a self-administered questionnaire. Tumor DNA methylation was categorized as present or absent based on analyses using bisulphite modification with real time methylation-specific polymerase chain reaction. Methylation measurement was possible for only 803 women because of tumor sample availability and participant refusal. After excluding women missing physical activity data (n=14), the final analyses included 789 women. Unconditional binary logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) from case-case analyses with and without adjustment for potential confounders. PA was categorized for analysis as 6 hours/week, using <3 hours/week as the reference category. Statistical interaction of PA with menopausal status and obesity was examined by including one-way interaction terms in the multivariable logistic regression model and also by stratified analysis. Results: There was a positive association between physical activity and DNA methylation status of at least one of the three genes. Compared to women who reported PA 6 hours/week were 1.69 (1.12-2.55) and 1.55 (1.03-2.35), respectively. There was a statistically non-significant positive association for 3-6 hours/week and >6 hours/week of physical activity for E-Cadherin [OR = 1.26, 95% CI: 0.72-2.01; and OR = 1.34, 95% CI: 0.80-2.24], p16 [OR = 1.22, 95% CI: 0.77-1.93; and OR = 1.13, 95% CI: 0.71-1.79] and RAR-β2 [OR = 1.37, 95% CI: 0.87-2.17; and OR = 1.23, 95% CI: 0.78-1.95]. The association between PA and DNA methylation did not differ between pre- and post-menopausal women or according to BMI (median cut point) status for the three genes analyzed together individual genes or individual genes.;Conclusion: The results suggest that lifetime physical activity may increase DNA methylation.