Estrogen receptor β polymorphism is associated with prostate cancer risk

Purpose: After cloning of the second estrogen receptor, estrogen receptor beta (ER beta) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ER beta is thought to exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ER beta gene are associated with prostate cancer risk. Experimental Design: We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ER gene from the promoter to the T-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects. Results: There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen. Conclusion: We found an association with a SNP located in the promoter region of the ER beta gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ER beta is of importance for risk of prostate cancer.