Luminal long non-coding RNAs regulated by estrogen receptor alpha in a ligand-independent manner show functional roles in breast cancer
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Valentina Miano1,2, Giulio Ferrero1,2,3, Stefania Reineri1,2,4, Livia Caizzi1,6, Laura Annaratone5, Laura Ricci1,2, Santina Cutrupi1,2, Isabella Castellano5, Francesca Cordero1,3, Michele De Bortoli1,2
1Center for Molecular Systems Biology, University of Turin, Turin, Italy
2Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
3Department of Computer Science, University of Turin, Turin, Italy
4Bioindustry Park Silvano Fumero, Turin, Italy
5Department of Medical Sciences, University of Turin, Turin, Italy
6Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Michele De Bortoli, e-mail: [email protected]
Keywords: lncRNA, breast cancer, estrogen receptor, data integration, DSCAM-AS1
Received: August 05, 2015 Accepted: November 16, 2015 Published: November 28, 2015
Estrogen Receptor alpha (ERα) activation by estrogenic hormones induces luminal breast cancer cell proliferation. However, ERα plays also important hormone-independent functions to maintain breast tumor cells epithelial phenotype. We reported previously by RNA-Seq that in MCF-7 cells in absence of hormones ERα down-regulation changes the expression of several genes linked to cellular development, representing a specific subset of estrogen-induced genes. Here, we report regulation of long non-coding RNAs from the same experimental settings. A list of 133 Apo-ERα-Regulated lncRNAs (AER-lncRNAs) was identified and extensively characterized using published data from cancer cell lines and tumor tissues, or experiments on MCF-7 cells. For several features, we ran validation using cell cultures or fresh tumor biopsies. AER-lncRNAs represent a specific subset, only marginally overlapping estrogen-induced transcripts, whose expression is largely restricted to luminal cells and which is able to perfectly classify breast tumor subtypes. The most abundant AER-lncRNA, DSCAM-AS1, is expressed in ERα+ breast carcinoma, but not in pre-neoplastic lesions, and correlates inversely with EMT markers. Down-regulation of DSCAM-AS1 recapitulated, in part, the effect of silencing ERα, i.e. growth arrest and induction of EMT markers. In conclusion, we report an ERα-dependent lncRNA set representing a novel luminal signature in breast cancer cells.
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