Oxidative stress, genetic polymorphisms and breast cancer risk
Quick, Sylvia K.
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Oxidative stress is believed to play an important role in the development and progression of breast cancer. Three central enzymes in oxidative stress pathways are manganese superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPX1). For each enzyme, a single functional genetic polymorphism was selected and the genotypes determined for women in the Western New York Exposures and Breast Cancer study, a population-based case-control study. Cases (n=1170) were women with primary, incident, pathologically confirmed postmenopausal breast cancer. Randomly selected controls (n=2115) were frequency matched to cases on age and race. Extensive information was collected on potential confounders and effect modifiers, such as diet, alcohol use and hormone use. Genotypes were assayed by MALDI-TOF. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounders. A single genotype alone was not associated with breast cancer risk for any of the three genes. GPX1 TT genotype was associated with an increased risk of breast cancer among those who also had the SOD2 CC genotype (OR 2.15, 95% CI 1.07-4.34). We stratified on several lifestyle factors; SOD2 genotype was associated with breast cancer risk among premenopausal women with low BMI. The association of CAT genotype with risk among postmenopausal women differed by level of alcohol consumption, with increased risk associated with CT/TT genotype among women reporting higher alcohol consumption. The associations of both CAT and GPX1 with postmenopausal breast cancer risk depended upon use of hormone replacement therapy. The relationship between CAT genotype, hormone replacement therapy and breast cancer risk was investigated in detail. Ever use of hormone replacement therapy was associated with an increase in risk (OR 1.39, 95% CI 1.11-1.75). The increased risk associated with ever use was more pronounced among those with the variant CT or TT CAT genotypes (OR 1.88, 95% CI 1.29-2.75) than among those with the common CC genotype (OR 1.15, 95% CI 0.86-1.54). Similarly, risk associated with five or more years of HRT use was greater among those with at least one variant T allele (OR 2.32, 95% CI 1.50-3.59). Increased risk was restricted to estrogen receptor positive breast cancer. Our findings suggest that, while none of the three genotypes significantly impact breast cancer risk when considered in isolation, simultaneous consideration of genotype of oxidative stress genes and environmental exposure revealed that genotype may be a significant breast cancer risk factor for certain subgroups of women. This observation provides insight into the etiology of breast cancer, suggesting that oxidative stress plays a role in breast carcinogenesis.