Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis

Oncogene. 2008 Feb 21;27(9):1218-30. doi: 10.1038/sj.onc.1210741. Epub 2007 Aug 27.


To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFbeta exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGFbeta-receptor-I kinase inhibitor or withdrawal of TGFbeta for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGFbeta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFbeta withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGFbeta1 (CHO-TGFbeta1) allowed outgrowth of epithelioid cells in CHO-TGFbeta1 cell-induced tumours. These epithelial islands enhanced CHO-TGFbeta1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGFbeta signalling in TD cells may permit TGFbeta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGFbeta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / genetics
  • CHO Cells
  • Cell Culture Techniques
  • Cell Line
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Cricetinae
  • Cricetulus
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Female
  • Genes, Tumor Suppressor / physiology
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mesoderm / pathology*
  • Mice
  • Signal Transduction / physiology*
  • Smad Proteins / antagonists & inhibitors*
  • Smad Proteins / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*


  • Smad Proteins
  • Transforming Growth Factor beta