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Mol Endocrinol. 2007 May;21(5):1132-47. Epub 2007 Feb 20.

The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines.

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1
Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030, USA.

Abstract

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)alpha-negative breast cancer, regulates the expression of ERalpha. Two putative miR-206 sites, (hERalpha1 and hERalpha2), were found in silico within the 3'-untranslated region of human ERalpha mRNA. Transfection of MCF-7 cells with pre-miR-206 or 2'-O-methyl antagomiR-206 specifically decreased or increased, respectively, ERalpha mRNA levels. Overexpression of pre-miR-206 reduced ERalpha and beta-actin protein levels, with no effect on ERbeta, E-cadherin, or glyceraldehyde-3-phosphate dehydrogenase. Reporter constructs containing the hERalpha1 or hERalpha2 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 C-->T single nucleotide polymorphism in the hERalpha1 site increased repression of luciferase activity to approximately 3.3-fold in HeLa cells. MiR-206 levels were higher in ERalpha-negative MB-MDA-231 cells than ERalpha-positive MCF-7 cells, but only the ERalpha1 site mediated significantly more repression in reporter constructs. MiR-206 expression was strongly inhibited by ERalpha agonists, but not by an ERbeta agonist or progesterone, indicating a mutually inhibitory feedback loop. These findings provide the first evidence for the posttranscriptional regulation of ERalpha by a micro-RNA in the context of breast cancer.

PMID:
17312270
DOI:
10.1210/me.2007-0022
[Indexed for MEDLINE]

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