MicroRNAs (
miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their
messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in
miRNA target sites. Here, we selected 11
miRNA target site SNPs located in
3' untranslated regions of genes involved in
cancer and
breast cancer to analyze their impact on
breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a
miRNA target site in the
estrogen receptor (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41-0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces
breast cancer risk. Thus,
therapies that inhibit ESR1 are used for
breast cancer treatment. According to in silico analysis, ESR1_rs2747648 affects the binding capacity of miR-453, which is stronger when the C allele is present. In contrast, the T allele attenuates the binding of miR-453, which might lead to a reduced
miRNA-mediated ESR1 repression, in consequence higher ESR1
protein levels and an increased
breast cancer risk. Thus, the
breast cancer protective effect observed for the C allele in premenopausal women is biologically reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome.