title: 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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Hou-Wei
authors.initials: HW
authors.lastname: Chu
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chou
authors.forename: Ling-Yueh
authors.initials: LY
authors.lastname: Hu
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Pei-Ei
authors.initials: PE
authors.lastname: Wu
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002884:Chromosomes, Human, Pair 15; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C576613:MIRN190 microRNA, human; D035683:MicroRNAs; D044463:Receptor, PAR-1; D004958:Estradiol