title: miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling.
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.
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Rita
authors.initials: R
authors.lastname: El Helou
authors.affiliation: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pinna
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wicinski
authors.affiliation: Université Grenoble-Alpes, 38000 Grenoble, France; CEA, iRTSV, Biologie à Grande Echelle, 38054 Grenoble, France; INSERM, U1038, 38054 Grenoble, France.
authors.forename: Ricky
authors.initials: R
authors.lastname: Bhajun
authors.affiliation: Université Grenoble-Alpes, 38000 Grenoble, France; CEA, iRTSV, Biologie à Grande Echelle, 38054 Grenoble, France; INSERM, U1038, 38054 Grenoble, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guyon
authors.affiliation: Plateform Integrative Bioinformatics, Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Cibi, 13273 Marseille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rioualen
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Abigaelle
authors.initials: A
authors.lastname: Gros
authors.affiliation: CNRS, Institute of Molecular and Cellular Pharmacology, Sophia Antipolis, 06560 Valbonne, France; University of Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.affiliation: CNRS, Institute of Molecular and Cellular Pharmacology, Sophia Antipolis, 06560 Valbonne, France; University of Nice Sophia Antipolis, 06000 Nice, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Plateform Integrative Bioinformatics, Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Cibi, 13273 Marseille, France.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Bidaut
authors.affiliation: 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.
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D035683:MicroRNAs; D051153:Wnt Proteins; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase