Fibroblast growth factor 8 induced downregulation of thrombospondin 1 is mediated by the MEK/ERK and PI3K pathways in breast cancer cells

Growth Factors. 2010 Aug;28(4):256-67. doi: 10.3109/08977191003745480.

Abstract

Expression of fibroblast growth factor 8 (FGF-8) is increased in several forms of hormonal cancer. It was previously shown to regulate expression of thrombospondin 1 (TSP-1), an inhibitor of angiogenesis, in S115 breast cancer cells. Here, we studied the FGF-8-activated signalling pathways mediating TSP-1 repression in S115 cells and in non-tumorigenic MCF10A cells. Inhibition of FGF receptors or of MEK1/2 and PI3K with specific inhibitors (PD173074, U0126 or LY294002, respectively) restored TSP-1 mRNA expression in the presence of FGF-8 in S115 cells. Furthermore, U0126 and LY294002 increased TSP-1 mRNA expression in S115 cells over-expressing FGF-8. In MCF10A cells, FGF-8 treatment also decreased TSP-1 expression and the effect was dependent on active MEK1/2. In conclusion, FGF-8 suppresses TSP-1 expression through two independent pathways, MEK1/2 and PI3K. Repression of TSP-1 may be an important mechanism involved in induction of an angiogenic phenotype and growth of FGF-8-expressing breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Modulating Agents / metabolism
  • Animals
  • Blotting, Western
  • Breast Neoplasms
  • Butadienes / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblast Growth Factor 8 / genetics
  • Fibroblast Growth Factor 8 / metabolism*
  • Fibroblast Growth Factor 8 / pharmacology
  • Gene Expression
  • Humans
  • MAP Kinase Kinase 1 / metabolism*
  • MAP Kinase Kinase 2 / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Polymerase Chain Reaction
  • Pyrimidines / pharmacology
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction*
  • Thrombospondin 1 / metabolism*

Substances

  • Angiogenesis Modulating Agents
  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Nitriles
  • PD 173074
  • Pyrimidines
  • Recombinant Proteins
  • Thrombospondin 1
  • U 0126
  • Fibroblast Growth Factor 8
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Map2k2 protein, mouse