NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression

Abstract

The transcription factor NF-B is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-B in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-. We show here that the IKK-2/IB/NF-B pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-B signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-. Furthermore, inhibition of NF-B activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-B is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-B activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-B during distinct steps of breast cancer progression and suggest that the cooperation of Ras-and TGF--dependent signaling pathways in late-stage tumorigenesis depends critically on NF-B activity.