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

• Published in: Cell reports (Cambridge) Vol. 18; no. 9; pp. 2256 - 2268
• Main Authors: El Helou, Rita, Pinna, Guillaume, Cabaud, Olivier, Wicinski, Julien, Bhajun, Ricky, Guyon, Laurent, Rioualen, Claire, Finetti, Pascal, Gros, Abigaelle, Mari, Bernard, Barbry, Pascal, Bertucci, Francois, Bidaut, Ghislain, Harel-Bellan, Annick, Birnbaum, Daniel, Charafe-Jauffret, Emmanuelle, Ginestier, Christophe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.02.2017; Elsevier
• Subjects: Biochemistry, Molecular Biology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Differentiation - genetics; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic - genetics; Genomics; Humans; Life Sciences; MicroRNAs - genetics; Neoplastic Stem Cells - pathology; Signal Transduction - physiology; Stearoyl-CoA Desaturase - genetics; Wnt Proteins - genetics; Wnt Signaling Pathway - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.016

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. [Display omitted] •miR-600 expression balances self-renewal and differentiation of bCSCs•miR-600 acts as a regulator of WNT signaling through SCD1 modulation•Low miR-600 expression in breast tumors is associated with poor prognosis El Helou et al. identify miRNAs that are able to balance bCSC fate. They find that miR-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal. miR-600 was further found to regulate WNT signaling through SCD1, and miR-600 expression correlates with clinical outcome.