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The Micro-Ribonucleic Acid (miRNA) miR-206 Targets the Human Estrogen Receptor- (ER) and Represses ER Messenger RNA and Protein Expression in Breast Cancer Cell Lines

Department of Cell Biology (B.D.A., B.A.W.) and Department of Molecular, Microbial and Structural Biology and Center for Vascular Biology (H.F.), University of Connecticut Health Center, Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: Bruce White, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030. E-mail: BWhite{at}nso2.uchc.edu.

Micro-RNAs are small noncoding RNAs, which diminish the stability and/or translation of mRNAs. This study examined whether miR-206, previously shown to be elevated in estrogen receptor (ER)-negative breast cancer, regulates the expression of ER. Two putative miR-206 sites, (hER1 and hER2), were found in silico within the 3'-untranslated region of human ER mRNA. Transfection of MCF-7 cells with pre-miR-206 or 2'-O-methyl antagomiR-206 specifically decreased or increased, respectively, ER mRNA levels. Overexpression of pre-miR-206 reduced ER and ß-actin protein levels, with no effect on ERß, E-cadherin, or glyceraldehyde-3-phosphate dehydrogenase. Reporter constructs containing the hER1 or hER2 binding sites inserted into the 3'-untranslated region of the luciferase mRNA conferred a 1.6- and 2.2-fold repression of luciferase activity, respectively, in HeLa cells. Both miR-206 sites responded accordingly to exogenous hsa-pre-miR-206 and 2'-O-methyl antagomiR-206, and both sites were rendered inactive by mutations that disrupted hybridization to the 5'-seed of miR-206. A CT single nucleotide polymorphism in the hER1 site increased repression of luciferase activity to approximately 3.3-fold in HeLa cells. MiR-206 levels were higher in ER-negative MB-MDA-231 cells than ER-positive MCF-7 cells, but only the ER1 site mediated significantly more repression in reporter constructs. MiR-206 expression was strongly inhibited by ER agonists, but not by an ERß agonist or progesterone, indicating a mutually inhibitory feedback loop. These findings provide the first evidence for the posttranscriptional regulation of ER by a micro-RNA in the context of breast cancer.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol  |  Progesterone

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