A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis

To identify microRNAs that are important in regulating breast cancer progression, the present study used data for the 199 961 single-nucleotide polymorphisms (SNPs) in 837 breast cancer patients genotyped in a recent genome-wide association study to identify loci associated with lymph node metastasis (LNM). SNPs tagging the 15q22.2 locus showed a significant association with LNM and miR-190a was found to be the only microRNA in this region. The role of miR-190a in LNM was supported by the findings that increased miR-190a expression inhibited cell migration and invasiveness and that the target of miR-190a was protease-activated-receptor 1 (PAR-1), which is a metastasis promoting protein in several cancers. In addition, the promoter region of miR-190a was defined and found to contain half of an estrogen response element, suggesting that miR-190a is regulated by estrogen receptor (ER) signaling. This was confirmed by the findings that miR-190a expression was activated by 17 beta-estradiol and that ER alpha bound directly to this promoter. The importance of this ER alpha-miR190a-PAR-1 link in breast tumorigenesis is suggested by the findings of (i) an association between genetic polymorphism of the miR-190a-containing region and LNM that is modified by SNPs of PAR-1 and is particularly significant in ER alpha-positive patients and (ii) a combined effect of ER alpha and miR-190a expression on tumor grade/cancer stage. More importantly, the level of miR-190a expression in primary breast carcinomas correlated with overall survival. These findings suggest a novel pathway in which ER alpha signaling regulates miR-190a expression, causing inhibition of PAR-1 expression, correlated with inhibition of cancer metastasis.