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

Abstract

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 17β-estradiol and that ERα bound directly to this promoter. The importance of this ERα-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 ERα-positive patients and (ii) a combined effect of ERα 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 ERα signaling regulates miR-190a expression, causing inhibition of PAR-1 expression, correlated with inhibition of cancer metastasis.

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

“…This result provides strong evidence for us to further explore the role of ceRNA regulatory networks in LN metastasis. In a previous study [37], miR190 was found to be the only miRNA identified by a genome-wide association study in the loci associated with LN metastasis of breast cancer. Our findings support the notion that miR190 functions as a metastasis suppressor, significantly reducing invasiveness, migration and lymphangiogenesis by regulating LNMICC expression.…”

Dysregulation of microRNAs in triple-negative breast cancer

“…In breast cancer, overexpression of miR-190a has inhibited the cell migration and invasiveness. Moreover, miR-190a expression in primary breast carcinomas correlated with overall survival [29]. Nevertheless, the role of miR-190a in breast cancer biology is still unclear.…”

The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells

“…Functional studies have linked oestrogen-induced deregulation of miRNA with phenotypic changes that contribute to breast carcinogenesis (Castellano et al, 2009;Chu et al, 2014;Pinho et al, 2013). Consequently, it is possible that aberrant miRNA expression induced by activation of ERα by PhIP could be an important factor in the carcinogenesis induced by the chemical.…”