Modifying effects of oxidative stress and DNA repair variants on physical activity and breast cancer risk

Purpose. The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Physical activity may also improve damage repair systems, particularly those that operate on oxidative damage. Given the paradoxical and complex effects of physical activity both oxidative stress and DNA repair pathways are of interest. Polymorphisms in these pathways may modify the association between RPA and breast cancer incidence. Methods. We estimated interactions between RPA and several polymorphisms in oxidative stress-related genes (CAT, COMT, GPX, GSTP1, GSTA1, GSTM1, GSTP1, MPO, and MnSOD) as well as DNA repair genes (ERCC1, MGMT, MLH1, MSH2, MSH3, OGG1, XPA, XPC, XPD, XPF, XPG, and XRCC1). Data were from the Long Island Breast Cancer Study Project, a population-based, case-control study with interview and biomarker data available on 1053 cases and 1102 controls. Results. Six variants in antioxidant and DNA repair pathway genes (CAT rs1001179, GSTP1-Ile105Val, XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val) interacted with postmenopausal RPA (p=0.043, 0.006, 0.048, 0.022, 0.012, and 0.010, respectively). Highly active women with genotypes related to reduced antioxidant capacity were at increased risk of breast cancer (CAT OR=1.61; 95% CI, 1.06-2.45) while risk reductions were observed among moderately active women with genotypes related to enhanced antioxidant capacity (GSTP1 OR=0.56; 95% CI, 0.38-0.84). With respect to DNA repair we found risk reductions for highly active women with common genotypes for XPC (OR=0.57; 95% CI, 0.38-0.84) and XPF (OR=0.64; 95% CI, 0.46-0.89) compared to non-active women homozygous for the major alleles. Non-significant risk reductions were observed among active women with at least one variant allele for XPG and MLH1, respectively. Conclusions. Genes involved in antioxidant and DNA repair pathways may modify the RPA-breast cancer risk association. While the functional significance of many polymorphisms with respect to breast cancer remains largely unknown, the observed associations are biologically plausible and consistent across multiple indicators of physical activity reducing the likelihood that these findings are attributable to chance. Our results merit further investigation.