This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-2206v1 69/21/8332    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maillot, G. Articles by Vagner, S. PubMed PubMed Citation Articles by Maillot, G. Articles by Vagner, S.

Widespread Estrogen-Dependent Repression of microRNAs Involved in Breast Tumor Cell Growth

¹ Institut National de la Sante et de la Recherche Medicale U563, ² Institut Claudius Regaud, and ³ Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; ⁴ Institut National de la Sante et de la Recherche Medicale, UMRS 940, Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris, France; and ⁵ Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany

Requests for reprints: Stéphan Vagner, Institut National de la Sante et de la Recherche Medicale U563, Institut Claudius Regaud, 20-24 Rue du Pont St-Pierre, 31052 Toulouse, France. Phone: 33-567696311; Fax: 33-561424631; E-mail: stephan.vagner{at}inserm.fr.

Altered expression of microRNAs (miRNA), an abundant class of small nonprotein-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 reverse transcription-PCR (RT-PCR) 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. Overall, our data indicate that the extensive alterations in miRNA regulation upon estrogen signaling pathway play a key role in estrogen-dependent functions and highlight the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. [Cancer Res 2009;69(21):8332–40]

Key Words: Estrogen • breast cancer • microRNAs