Cluster 503 Gene −-Activating miR 424 β Expression of a Heterogeneous TGF Metastatic Heterogeneity of Breast Cancer Cells Is Associated with

TGFb signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFb activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFb signaling can be overactivated and sustained. To better understand how the TGFb inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424–503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFb signaling, leading to enhanced TGFb signaling and metastatic capability of breast cancer cells. Moreover, antagonizingmiR424–503 in breast cancer cells suppressedmetastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424–503 cluster contributed to the heterogeneity of TGFb activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novelmechanism,mediated by elevated expression of themiR424–503 cluster, underlying TGFb activation and metastasis of human breast cancer. Cancer Res; 74(21); 6107–18. 2014 AACR.