Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity.

Abstract

Introduction: Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant.

Methods: We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m²]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation.

Results: BMI 25-29.9kg/m², and perhaps BMI≥30kg/m², was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m² were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84).

Discussion: While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.