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

Mesenchymal stem/stromal cells (MSCs) are pro- genitor 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 re- sponses of breast cancer cells (BCCs) to MSC influ- ences remain incompletely understood. Here, we show that MSCs cause aberrant expression of micro- RNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated micro- RNAs 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 propaga- tion, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malig- nant clinical breast cancer and are associated signif- icantly with poor survival. Our results identify molec- ular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.