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This version published online on March 13, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0022
Molecular Endocrinology Vol. 0, No. 2007 200700222-
doi:10.1210/me.2007-0022
Copyright © 2007 by the Endocrine Society.
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Submitted on January 15, 2007
Accepted on February 15, 2007

The micro-RNA miR-206 Targets the Human Estrogen Receptor-{alpha}, and Represses ER{alpha} mRNA and Protein Expression in Breast Cancer Cell Lines

Brian D. Adams, Henry Furneaux, and Bruce White*

Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT. 06030, and; Department of Molecular, Microbial and Structural Biology and Center for Vascular Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT. 06030

* To whom correspondence should be addressed. E-mail: BWhite{at}nso2.uchc.edu.

MicroRNAs (miRNAs) are small noncoding RNAs, which diminish the stability and/or translation of messenger RNAs (mRNAs). This study examined whether miR-206, previously shown to be elevated in ER{alpha}-negative breast cancer, regulates the expression of ER{alpha}. Two putative miR-206 sites, (hER{alpha}1 and hER{alpha}2), were found in silico within the 3' untranslated region (3' UTR) of human ER{alpha} mRNA. Transfection of MCF-7 cells with pre-miR-206 or 2'-O-methyl antagomiR-206 specifically decreased or increased, respectively, ER{alpha} mRNA levels. Overexpression of pre-miR-206 reduced ER{alpha} and {beta}-actin protein levels, with no effect on ER{beta}, E-cadherin or GAPDH. Reporter constructs containing the hER{alpha}1 or hER{alpha}2 binding sites inserted into the 3' UTR 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 224 T single nucleotide polymorphism (SNP) in the hER{alpha}1 site increased repression of luciferase activity to ~3.3 fold in HeLa cells. MiR-206 levels were higher in ER{alpha}-negative MB-MDA-231 cells, than ER{alpha}-positive MCF-7 cells, but only the ER{alpha}1 site mediated significantly more repression in reporter constructs. MiR-206 expression was strongly inhibited by ER{alpha} agonists, but not by an ER{beta} agonist or progesterone, indicating a mutually-inhibitory feedback loop. These findings provide the first evidence for the posttranscriptional regulation of ER{alpha} by a miRNA in the context of breast cancer.
Key words: Estrogen Receptor • Single Nucleotide Polymorphism • microRNA • miR-206 • Breast Cancer

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Ligands:   17β-Estradiol  |  Progesterone



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