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.
Bibliographical noteFunding Information:
We thank J. Love, J.-A. Kwon, and S. Gupta for miRNA profiling data analysis; A. Contreras for assistance in animal studies; K. Groglio and M. Fahlberg for FACS sorting assistance; D. Louvard for assistance in clinical specimen procurement; and P. Pandolfi and P. Provero for helpful discussions. This work was supported by start-up funds from BIDMC (A.E.K.), the Sidney Kimmel Cancer Research Foundation (A.E.K.), the Susan G. Komen For The Cure (A.E.K.), AIRC IG14201 (D.T.), Compagnia di San Paolo, 2008.1054 (D.T.), and Progetto Ricerca Ateneo Torino (D.T.). Human BM-MSCs were provided by the Texas A&M Health Science Center (CMI for Regenerative Medicine at Scott & White) through NIH P40RR017447. B.G.C. is a 2012 American Cancer Society Postdoctoral Fellow. F.O. is a recipient of FIRB giovani 2008 (RBFR08F2FS-276 002). A.E.K. is a 2010 Kimmel Scholar, a recipient of a Career Development Award from the BIDMC Prostate and Breast Cancer Research Program, and a recipient of a 2012 Career Catalyst Research Award from Susan G. Komen For The Cure.
© 2014 Elsevier Inc.