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

• Main Authors: Rita El Helou, Guillaume Pinna, Olivier Cabaud, Julien Wicinski, Ricky Bhajun, Laurent Guyon, Claire Rioualen, Pascal Finetti, Abigaelle Gros, Bernard Mari, Pascal Barbry, Francois Bertucci, Ghislain Bidaut, Annick Harel-Bellan, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Christophe Ginestier
• Format: Article
• Language: English
• Published: Elsevier 2017-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471730181X

Summary: 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. : 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.