rs15869 at miRNA binding site in BRCA2 is associated with breast cancer susceptibility

BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3' untranslated region (3'-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case-control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3'-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student's t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene-reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141-2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene-reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130-0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.