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The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response.

ABSTRACT: Following estrogenic activation, the estrogen receptor-alpha (ERalpha) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERalpha have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERalpha, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17-92 and mir-106a-363. Characterization of the mir-17-92 locus confirms that the ERalpha target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17-92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17-92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ERalpha-positive compared to ERalpha-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri-miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ERalpha, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ERalpha transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ERalpha, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.

SUBMITTER: Castellano L

PROVIDER: S-EPMC2747188 | biostudies-other | 2009 Sep

REPOSITORIES: biostudies-other

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The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response.

Castellano Leandro L Giamas Georgios G Jacob Jimmy J Coombes R Charles RC Lucchesi Walter W Thiruchelvam Paul P Barton Geraint G Jiao Long R LR Wait Robin R Waxman Jonathan J Hannon Gregory J GJ Stebbing Justin J

Proceedings of the National Academy of Sciences of the United States of America 20090824 37

Following estrogenic activation, the estrogen receptor-alpha (ERalpha) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERalpha have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERalpha, which include upregulation of miRNAs derived ...[more]

PMID: 19706389

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Project description:BackgroundEstrogens are known to regulate the proliferation of breast cancer cells and to modify their phenotypic properties. Identification of estrogen-regulated genes in human breast tumors is an essential step toward understanding the molecular mechanisms of estrogen action in cancer. To this end we generated and compared the Serial Analysis of Gene Expression (SAGE) profiles of 26 human breast carcinomas based on their estrogen receptor alpha (ER) status. Thus, producing a breast cancer SAGE database of almost 2.5 million tags, representing over 50,000 transcripts.ResultsWe identified 520 transcripts differentially expressed between ERalpha-positive (+) and ERalpha-negative (-) primary breast tumors (Fold change >or= 2; p < 0.05). Furthermore, we identified 220 high-affinity Estrogen Responsive Elements (EREs) distributed on the promoter regions of 163 out of the 473 up-modulated genes in ERalpha (+) breast tumors. In brief, we observed predominantly up-regulation of cell growth related genes, DNA binding and transcription factor activity related genes based on Gene Ontology (GO) biological functional annotation. GO terms over-representation analysis showed a statistically significant enrichment of various transcript families including: metal ion binding related transcripts (p = 0.011), calcium ion binding related transcripts (p = 0.033) and steroid hormone receptor activity related transcripts (p = 0.031). SAGE data associated with ERalpha status was compared with reported information from breast cancer DNA microarrays studies. A significant proportion of ERalpha associated gene expression changes was validated by this cross-platform comparison. However, our SAGE study also identified novel sets of genes as highly expressed in ERalpha (+) invasive breast tumors not previously reported. These observations were further validated in an independent set of human breast tumors by means of real time RT-PCR.ConclusionThe integration of the breast cancer comparative transcriptome analysis based on ERalpha status coupled to the genome-wide identification of high-affinity EREs and GO over-representation analysis, provide useful information for validation and discovery of signaling networks related to estrogen response in this malignancy.

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The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response.

Publications

The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response.

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