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

• Published in: The Journal of clinical investigation Vol. 114; no. 4; pp. 569 - 581
• Main Authors: Huber, Margit A., Azoitei, Ninel, Baumann, Bernd, Grünert, Stefan, Sommer, Andreas, Pehamberger, Hubert, Kraut, Norbert, Beug, Hartmut, Wirth, Thomas
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 16.08.2004
• ISSN: 0021-9738
• DOI: 10.1172/JCI200421358

The transcription factor NF-κB 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-κB 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-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB 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-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB 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-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-β–dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity.