MicroRNA-608Impacts Susceptibility And Progress Of HER2-positive Breast Cancer

BackgroundPrevious bioinformatic analyses have shown that human microRNA-608may represses the expression of various target oncogenes, while germline genetic polymorphism rs4919510:C>G in mature sequence of microRNA-608could reduce the repression. It suggests that microRNA-608and polymorphism rs4919510:C>G might be associated with biological progress of breast cancer. In this study, we investigated the effect of microRNA-608and polymorphism rs4919510:C>G in breast cancer, and surveyed to reveal potential pathological mechanism.Methodsrs4919510:C>G was genotyped in1,138breast cancer patients and1,934community-based controls, and its associations with breast cancer and pathologic features were investigated. HR were estimated by logistic regression. Predicted targets of miR-608and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism. Proliferation and invasion of breast cancer cell lines were tested by proliferation and invasion assay. The potential microRNA-608target genes were investigated by Western Blot.ResultsAlthough rs4919510:C>G was unrelated to breast cancer in general patients, variant genotype (CG/GG) was specifically associated with increased risk of HER2-positive subtype (HR=1.77,95%CI,1.22-2.58in recessive model). Variant G-allele was the risk allele with OR of1.55(95%CI,1.18-2.04). Patients carrying GG-genotype also had larger HER2-positive tumors (P=0.006). Bioinformatic analyses indicated that HSF1which is required for HER2-induced tumorigenesis and proliferation, might be a target of miR-608. The minimum free-energy of ancestral-miR-608(C-allele) binding to HSF1is-35.9kcal/mol, while that of variant-form (G-allele) is-31.5kcal/mol, indicating a lower affinity of variant-miR-608to HSF1mRNA. We subsequently tested the proliferative and invasive abilities of breast cancer cell lines. It proves the results of case-control study that microRNA-608and polymorphism rs4919510: C>G are associated with breast cancer proliferation but not invasion. The Western Blot shows that HER2-positive breast cancer with different genotype (CG/GG) had different HSF1protein level, which is accord with the cell proliferation assay.ConclusionThis study had found that microRNA-608is associated with susceptibility and progress in HER2-positive breast cancer, furthermore, microRNA-608could impact breast cancer proliferation via HSF1/HER2pathway.