NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression
Margit A. Huber, … , Hartmut Beug, Thomas Wirth
Margit A. Huber, … , Hartmut Beug, Thomas Wirth
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):569-581. https://doi.org/10.1172/JCI21358.
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Article Oncology

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

Abstract

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.

Authors

Margit A. Huber, Ninel Azoitei, Bernd Baumann, Stefan Grünert, Andreas Sommer, Hubert Pehamberger, Norbert Kraut, Hartmut Beug, Thomas Wirth

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TGF-β induces NF-κB activity in EpRas cells. (A) EpRas and EpRasXT cells...
TGF-β induces NF-κB activity in EpRas cells. (A) EpRas and EpRasXT cells were stimulated with TGF-β1 (5 ng/ml) for the indicated times. EMSA with whole-cell extracts (6 μg) was performed with an NF-κB–specific probe (upper panel) and with an octamer-specific probe (lower panel) used as a control. (B) NF-κB transcriptional activity. EpRas cells were transiently transfected in triplicate with a 3xκB.luc or β-globin-TATA reporter construct. At 20 hours after transfection, cells were treated with TGF-β1 (5 ng/ml) for the indicated times. Then, the luciferase activities of extracts were determined and were normalized based on Renilla luciferase expression. The ratio of 3xκB.luc and β-globin-TATA is shown. The expression level of unstimulated empty vector-infected EpRas cells was used as the reference luciferase activity and was arbitrarily set to 1. Means and standard deviations are representative of two independent experiments carried out in triplicate. Bars represent standard deviations.