Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth.
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 17beta-estradiol (E(2)). We show that the expression of a broad set of miRNAs decreases following E(2) treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E(2)-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E(2)-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.
Maillot
Gérard
G
Institut National de la Sante et de la Recherche Medicale U563, Institut Claudius Regaud, and Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Lacroix-Triki
Magali
M
Pierredon
Sandra
S
Gratadou
Lise
L
Schmidt
Sabine
S
Bénès
Vladimir
V
Roché
Henri
H
Dalenc
Florence
F
Auboeuf
Didier
D
Millevoi
Stefania
S
Vagner
Stéphan
S
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D010865:Pilot Projects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D016896:Treatment Outcome
D000730:Androstadienes; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004965:Estrogen Antagonists; D004967:Estrogens; D035683:MicroRNAs; D012333:RNA, Messenger; D013629:Tamoxifen; C056516:exemestane