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

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.

• Authors: Kati Tarkkonen, Johanna Ruohola, Pirkko Härkönen
• Journal: Growth factors (Chur, Switzerland) (Growth Factors) Vol. 28 Issue 4 Pg. 256-67 (Aug 2010) ISSN: 1029-2292 [Electronic] England
• PMID: 20370578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism, 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, pharmacology)
• Signal Transduction
• Thrombospondin 1 (metabolism)