Objective: In this study we aimed to investigate whether the PvuII, XbaI and B-variant polymorphisms in the estrogen receptor alpha gene (ER-alpha) are associated with an increased risk of breast cancer in postmenopausal women, and whether the effect of high estradiol (E2) levels on breast cancer risk is altered by these polymorphisms. The selection of these polymorphisms was based on previously published associations with osteoporosis and spontaneous abortions.
Methods: The effect of the three polymorphisms on breast cancer risk was studied using a case-cohort design nested within a large population-based cohort study (n = 9349) in the Netherlands (the DOM-cohort). In total 380 incident breast cancer cases and a subcohort of 422 women were genotyped by RFLP or ASO hybridization methods.
Results: Women with the PvuII pp genotype had a 1.5 times non significant increased risk of breast cancer (95% CI: 0.94-2.42; p(trend) = 0.09) compared to women with the PP genotype. The Pp or pp genotype in combination with high E2 levels raised breast cancer risk significantly when compared to women with low E2 levels and the PP genotype (RR=2.26; 95% CI: 1.24-4.13). This interaction was statistically significant on the multiplicative scale (p = 0.01). The XbaI genotype (RR(xx versus XX) = 1.19; 95% CI: 0.73-1.95) and the B' allele (RR(BB'+B'B' versus BB) = 0.87; 95% CI: 0.56-1.33) were not associated with breast cancer risk.
Conclusion: The results of this study suggest that the PvuII polymorphism in the ER-alpha, or another mutation in linkage disequilibrium with PvuII, in combination with high E2 levels increases breast cancer risk in postmenopausal women.