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Cell Rep. 2017 Feb 28;18(9):2256-2268. doi: 10.1016/j.celrep.2017.02.016.

miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling.

Author information

1
Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
2
Plateforme ARN interférence (PARi), Service de Biologie Intégrative et de Génétique Moléculaire, I2BC, UMR 9198, CEA Saclay, 91191 Gif-sur-Yvette, France; Université Paris-Sud, Gif-sur-Yvette, 91400 Orsay, France.
3
Université Grenoble-Alpes, 38000 Grenoble, France; CEA, iRTSV, Biologie à Grande Echelle, 38054 Grenoble, France; INSERM, U1038, 38054 Grenoble, France.
4
Plateform Integrative Bioinformatics, Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Cibi, 13273 Marseille, France.
5
CNRS, Institute of Molecular and Cellular Pharmacology, Sophia Antipolis, 06560 Valbonne, France; University of Nice Sophia Antipolis, 06000 Nice, France.
6
Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France. Electronic address: christophe.ginestier@inserm.fr.

Abstract

Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression.

PMID:
28249169
DOI:
10.1016/j.celrep.2017.02.016
[Indexed for MEDLINE]
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