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.

MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis

VOLINIA, Stefano;
2014

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.
Cuiffo, Benjamin G; Campagne, Antoine; Bell, George W.; Lembo, Antonio; Orso, Francesca; Lien, Evan C.; Bhasin, Manoj K.; Raimo, Monica; Hanson, Summer E.; Marusyk, Andriy; El Ashry, Dorraya; Hematti, Peiman; Polyak, Kornelia; Mechta Grigoriou, Fatima; Mariani, Odette; Volinia, Stefano; Vincent Salomon, Anne; Taverna, Daniela; Karnoub, Antoine E.
File in questo prodotto:
File Dimensione Formato  
cuiffoPIIS1934590914004524.pdf

accesso aperto

Descrizione: Full text editoriale
Tipologia: Full text (versione editoriale)
Licenza: PUBBLICO - Pubblico con Copyright
Dimensione 3.75 MB
Formato Adobe PDF
3.75 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2356330
Citazioni
  • ???jsp.display-item.citation.pmc??? 72
  • Scopus 131
  • ???jsp.display-item.citation.isi??? 126
social impact