Invasion and metastasis of a mammary tumor involves TGF-beta signaling

Int J Cancer. 2001 Jan 1;91(1):76-82. doi: 10.1002/1097-0215(20010101)91:1<76::aid-ijc1012>;2-8.


Several studies have correlated escape from TGF-beta-mediated cell cycle arrest with the tumorigenic phenotype. Most often, this escape from growth control has been linked to dysfunctional TGF-beta receptors or defects in the TGF-beta-mediated SMAD signaling pathway. In this report, we found that highly metastatic 4T1 mammary carcinoma cells express functional TGF-beta receptors capable of initiating SMAD-mediated transcription, yet are not growth inhibited by TGF-beta1. We further observed that TGF-beta directly contributes to the metastatic behavior of this cell line. Exposure to TGF-beta caused 4T1 cells to undergo morphological changes associated with the metastatic phenotype and invade more readily through collagen coated matrices. Furthermore, expression of a dominant negative truncated type II receptor diminished TGF-beta signaling and significantly restricted the ability of 4T1 cells to establish distant metastases. Our results suggest that regardless of 4T1 resistance to TGF-beta-mediated growth inhibition, TGF-beta signaling is required for tumor invasion and metastases formation.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Division
  • Cell Movement / drug effects
  • Collagen / metabolism
  • Cross-Linking Reagents / pharmacology
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • Genes, Dominant
  • Mammary Neoplasms, Animal / metabolism*
  • Mice
  • Mice, SCID
  • Microscopy, Confocal
  • Neoplasm Invasiveness
  • Phenotype
  • Plasmids / metabolism
  • Receptors, Transforming Growth Factor beta / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Transcription, Genetic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured


  • Cross-Linking Reagents
  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen