title: MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis.
abstract: Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Cuiffo
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Campagne
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Bell
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin and MBC, 10126 Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lembo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin and MBC, 10126 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Orso
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Lien
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin and MBC, 10126 Torino, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Raimo
authors.affiliation: Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53792, USA.
authors.forename: Summer E
authors.initials: SE
authors.lastname: Hanson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Marusyk
authors.affiliation: Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Dorraya
authors.initials: D
authors.lastname: El-Ashry
authors.affiliation: Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53792, USA.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Mechta-Grigoriou
authors.affiliation: Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Human Anatomy Branch, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.affiliation: Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin and MBC, 10126 Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: akarnoub@bidmc.harvard.edu.
authors.forename: Antoine E
authors.initials: AE
authors.lastname: Karnoub
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011379:Prognosis; D013060:Speech / Q000502:physiology; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; C531408:mirn199 microRNA, human