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

J Clin Invest. 2004 Aug;114(4):569-81. doi: 10.1172/JCI21358.


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

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Breast Neoplasms
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cell Transformation, Viral
  • Disease Models, Animal
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Epithelial Cells / transplantation
  • Gene Expression Regulation, Neoplastic
  • Immunohistochemistry
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mice
  • Mice, Nude
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Metastasis*
  • Neoplasm Transplantation
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / metabolism
  • Retroviridae / genetics
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology


  • NF-kappa B
  • Transforming Growth Factor beta
  • Oncogene Protein p21(ras)