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Cell Stem Cell. 2014 Dec 4;15(6):762-74. doi: 10.1016/j.stem.2014.10.001. Epub 2014 Oct 16.

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

Author information

1
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institut Curie, 75248 Paris Cedex 05, France.
3
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
4
Department of Molecular Biotechnology and Health Sciences, University of Turin and MBC, 10126 Torino, Italy.
5
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
6
Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53792, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
8
Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
9
Institut Curie, 75248 Paris Cedex 05, France.
10
Department of Morphology, Surgery and Experimental Medicine, Human Anatomy Branch, University of Ferrara, 44121 Ferrara, Italy.
11
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.

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.

PMID:
25515522
DOI:
10.1016/j.stem.2014.10.001
[Indexed for MEDLINE]
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