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.
View: Text | PDF
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

×

Figure 9

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of NF-κB activity prevents metastasis of EpRas cells. (A) EpR...
Inhibition of NF-κB activity prevents metastasis of EpRas cells. (A) EpRas cells infected with empty GFP vector (Empty) or TD-IκBα were injected (5 × 105 cells per injection) into the tail veins of nude mice (four animals per cell type), and mice were analyzed for the presence of lung metastases. Note large metastatic nodules (white arrows) in the lung from the mouse injected with EpRas cells that had been infected with empty vector (EpRas empty; left). (B) Metastases in lungs similar to those shown in A were quantified in serial sections to determine the mean numbers of metastases per lung (four lungs per cell type). (C) Hematoxylin and eosin staining of lungs from mice injected with EpRas cells that had been infected with empty vector or TD-IκBα. Note large metastases in the mouse injected with EpRas cells that had been infected with empty vector. Original magnification, ×10. (D) The same cells analyzed in A–C were injected (2 × 105 cells per injection site; four injection sites per animal) into the fat pads of nude mice (three animals per cell type), and total tumor weight was determined for each individual mouse after 3 weeks. Average total tumor weights are shown.