MiRNA-binding site functional polymorphisms in DNA repair genes RAD51, RAD52, and XRCC2 and breast cancer risk in Chinese population

摘要

RAD51, RAD52, and XRCC2 are all involved in DNA homologous recombinational repair, and there are interactions among those genes. Polymorphisms in 3'-UTR of DNA repair genes may change DNA repair capacity by regulating gene expression. However, potential regulatory variants affecting their expression remain largely unexplored. Five miRNA-binding site SNPs (rs7180135 and rs45549040 in RAD51, rs1051669 and rs7963551 in RAD52 and rs3218550 in XRCC2) selected by bioinformatics method were genotyped in 498 breast cancer (BC) patients and 498 matched controls in Chinese population. Association between SNPs and BC risk was analyzed by adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) in unconditional logistic regression model. Quantitative real-time (qRT) PCR and Western Blot assays were used to calculate the relative expression of RAD52 in recombinant plasmid-pGenesil-1-let-7b group and let-7b-inhibitor group. Gene-reproductive factors interactions were evaluated by multifactor dimensionality reduction (MDR) method. We found that individuals with AC (OR 0.684, 95% CI 0.492-0.951) and CC (OR 0.317, 95% CI 0.200-0.503) genotypes of rs7963551 had a significantly lower risk of breast cancer and qRT-PCR and Western Blot revealed that let-7b might downregulate the expression of RAD52 inMCF-7 and SKBR-3 cells. A significant interaction between the number of pregnancy (>= 2) and rs7963551 (A(rs7963551)) was found to increase breast cancer risk by 2.63-fold (OR 2.63; 95% CI 2.03-3.42). In summary, the miRNA-binding SNPs in DNA repair genes RAD51, RAD52, and XRCC2 and their interaction with reproductive factors might play important roles in the development of BC, and let-7b might downregulate RAD52 expression in MCF-7 and SKBR-3 cells.