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Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.

ABSTRACT: Select changes in microRNA (miRNA) expression correlate with estrogen receptor alpha (ER alpha) expression in breast tumors. miR-21 is higher in ER alpha positive than negative tumors, but no one has examined how estradiol (E(2)) regulates miR-21 in breast cancer cells. Here we report that E(2) inhibits miR-21 expression in MCF-7 human breast cancer cells. The E(2)-induced reduction in miR-21 was inhibited by 4-hydroxytamoxifen (4-OHT), ICI 182 780 (Faslodex), and siRNA ER alpha indicating that the suppression is ER alpha-mediated. ER alpha and ER beta agonists PPT and DPN inhibited and 4-OHT increased miR-21 expression. E(2) increased luciferase activity from reporters containing the miR-21 recognition elements from the 3'-UTRs of miR-21 target genes, corroborating that E(2) represses miR-21 expression resulting in a loss of target gene suppression. The E(2)-mediated decrease in miR-21 correlated with increased protein expression of endogenous miR-21-targets Pdcd4, PTEN and Bcl-2. siRNA knockdown of ER alpha blocked the E(2)-induced increase in Pdcd4, PTEN and Bcl-2. Transfection of MCF-7 cells with antisense (AS) to miR-21 mimicked the E(2)-induced increase in Pdcd4, PTEN and Bcl-2. These results are the first to demonstrate that E(2) represses the expression of an oncogenic miRNA, miR-21, by activating estrogen receptor in MCF-7 cells.

SUBMITTER: Wickramasinghe NS

PROVIDER: S-EPMC2677875 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

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Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.

Wickramasinghe Nalinie S NS Manavalan Tissa T TT Dougherty Susan M SM Riggs Krista A KA Li Yong Y Klinge Carolyn M CM

Nucleic acids research 20090305 8

Select changes in microRNA (miRNA) expression correlate with estrogen receptor alpha (ER alpha) expression in breast tumors. miR-21 is higher in ER alpha positive than negative tumors, but no one has examined how estradiol (E(2)) regulates miR-21 in breast cancer cells. Here we report that E(2) inhibits miR-21 expression in MCF-7 human breast cancer cells. The E(2)-induced reduction in miR-21 was inhibited by 4-hydroxytamoxifen (4-OHT), ICI 182 780 (Faslodex), and siRNA ER alpha indicating that ...[more]

PMID: 19264808

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Project description:Altered expression of microRNAs (miRNAs), an abundant class of small non-protein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real time RTPCR experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy thereby showing an estrogen-dependent in vivo regulation of miRNA expression. Overall, our data indicates that the extensive alterations in miRNA regulation upon estrogen signalling pathway plays a key role in estrogen-dependent functions and highlights the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. 9 samples analyzed. Triplicates were done. MCF-7+miR26a+E2 (n=1 to 3) ; MCF7+miRctrl+E2 (n=1 to 3) ; MCF7+miRctrl+vehicle (n=1 to 3). We generated pairwise comparisons using EASANA from GenoSplice technology: MCF-7+miR26a+E2 versus MCF7+miRctrl+E2 and MCF-7+miRctrl+E2 versus MCF7+miRctrl+vehicle. Fold change ≥1.5 were selected.

Dataset Information

Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.

Publications

Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.

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