Estrogen Mediated-Activation of miR-191/425 Cluster Modulates Tumorigenicity of Breast Cancer Cells Depending on Estrogen Receptor Status

Gianpiero Di Leva, Claudia Piovan, Pierluigi Gasparini, Apollinaire Ngankeu, Cristian Taccioli, Daniel Briskin, Douglas G. Cheung, Brad Bolon, Laura Anderlucci, Hansjuerg Alder, Gerard Nuovo, Meng Li, Marilena V. Iorio, Marco Galasso, Santhanam Ramasamy, Guido Marcucci, Danilo Perrotti, Kimerly A. Powell, Anna Bratasz, Michela GarofaloKenneth P. Nephew, Carlo M. Croce

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.

Original languageEnglish (US)
Article numbere1003311
JournalPLoS Genetics
Volume9
Issue number3
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Di Leva, G., Piovan, C., Gasparini, P., Ngankeu, A., Taccioli, C., Briskin, D., Cheung, D. G., Bolon, B., Anderlucci, L., Alder, H., Nuovo, G., Li, M., Iorio, M. V., Galasso, M., Ramasamy, S., Marcucci, G., Perrotti, D., Powell, K. A., Bratasz, A., ... Croce, C. M. (2013). Estrogen Mediated-Activation of miR-191/425 Cluster Modulates Tumorigenicity of Breast Cancer Cells Depending on Estrogen Receptor Status. PLoS Genetics, 9(3), [e1003311]. https://doi.org/10.1371/journal.pgen.1003311