miR-600 acts as a bimodal switch that regulates breast cancer stem cell fate through WNT signaling

Cell reports

Authors: El Helou, Rita; Pinna, Guillaume; Cabaud, Olivier; Wicinski, Julien; Bhajun, Ricky; Guyon, Laurent; Rioualen, Claire; Finetti, Pascal; Gros, Abigaelle; Mari, Bernard;
PMID: 28249169

Publisher: Elsevier

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.