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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

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Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to

K Lehmann1, E Janda, C E Pierreux

  • 1Signal Transduction, Imperial Cancer Research Fund, London WC2A 3PX, UK.

Genes & Development
|October 21, 2000
PubMed

Insights

Sustained Raf activation promotes cancer-like cell changes and invasive growth by inducing TGF-beta. While Raf-ERK signaling protects cells from apoptosis, it does not directly block TGF-beta

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • c-Raf-1 is a key Ras effector, activating the ERK MAP kinase pathway.
  • This pathway regulates normal growth and is implicated in oncogenic transformation.

Purpose of the Study:

  • To investigate the role of Raf activation in epithelial-mesenchymal transition and invasive growth.
  • To elucidate the interplay between Raf-ERK signaling and TGF-beta in cancer progression.

Main Methods:

  • Utilized an inducible Raf system in Madin-Darby canine kidney (MDCK) cells.
  • Assessed invasive growth in collagen gels and TGF-beta-induced apoptosis and growth inhibition.
  • Examined the influence of ERK on Smad protein function (nuclear translocation, DNA binding, transcriptional activation).

Main Results:

  • Sustained Raf activation induced an epithelial-to-mesenchymal transition and invasive growth.
  • Raf-induced invasive growth depended on an autocrine TGF-beta loop.
  • Raf activation inhibited TGF-beta-induced apoptosis but not growth retardation.
  • ERK did not significantly impair Smad2, Smad3, or Smad4 function.
  • Raf activation broadly protected cells from apoptotic stimuli, enhancing TGF-beta-mediated invasiveness.

Conclusions:

  • The Raf-MAP kinase pathway synergizes with TGF-beta to promote malignancy.
  • Raf activation enhances cellular invasiveness and survival, contributing to cancer progression.
  • The mechanism involves broad anti-apoptotic effects rather than direct impairment of TGF-beta-induced Smad signaling.

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