NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2

Oncogene. 2007 Feb 1;26(5):711-24. doi: 10.1038/sj.onc.1209808. Epub 2006 Jul 24.


The transcription factor nuclear factor kappa B (NF-kappaB) is constitutively active in both cancer cells and stromal cells of breast cancer; however, the precise role of activated NF-kappaB in cancer progression is not known. Using parental MCF10A cells and a variant that expresses the myoepithelial marker p63 stably overexpressing the constitutively active p65 subunit of NF-kappaB (MCF10A/p65), we show that NF-kappaB suppresses the expression of epithelial specific genes E-cadherin and desmoplakin and induces the expression of the mesenchymal specific gene vimentin. P65 also suppressed the expression of p63 and the putative breast epithelial progenitor marker cytokeratin 5/6. MCF10A/p65 cells were phenotypically similar to cells undergoing epithelial to mesenchymal transition (EMT). MCF10A/p65 cells failed to form characteristic acini in three-dimensional Matrigel. Analysis of parental and MCF10A/p65 cells for genes previously shown to be involved in EMT revealed elevated expression of ZEB-1 and ZEB-2 in MCF10A/p65 cells compared to parental cells. In transient transfection assays, p65 increased ZEB-1 promoter activity. Furthermore, MCF10A cells overexpressing ZEB-1 showed reduced E-cadherin and p63 expression and displayed an EMT phenotype. The siRNA against ZEB-1 or ZEB-2 reduced the number of viable MCF10A/p65 but not parental cells, suggesting the dependence of MCF10A/p65 cells to ZEB-1 and ZEB-2 for cell cycle progression or survival. MCF10A cells chronically exposed to tumor necrosis factor alpha (TNFalpha), a potent NF-kappaB inducer, also exhibited the EMT-like phenotype and ZEB-1/ZEB-2 induction, both of which were reversed following TNFalpha withdrawal.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blotting, Northern
  • Blotting, Western
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic*
  • Electrophoretic Mobility Shift Assay
  • Epithelial Cells / metabolism
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism*
  • Mesoderm / metabolism*
  • Mutagenesis, Site-Directed
  • NF-kappa B / physiology*
  • Neoplasm Invasiveness / pathology
  • Promoter Regions, Genetic / genetics
  • RNA, Small Interfering / pharmacology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Zinc Finger E-box-Binding Homeobox 1
  • Zinc Fingers


  • Cadherins
  • Homeodomain Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1