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
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Modulating Agents / metabolism
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Animals
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Blotting, Western
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Breast Neoplasms
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Butadienes / pharmacology
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Cell Line
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Cell Line, Tumor
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Chromones / pharmacology
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Down-Regulation / drug effects
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Fibroblast Growth Factor 8 / genetics
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Fibroblast Growth Factor 8 / metabolism*
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Fibroblast Growth Factor 8 / pharmacology
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Gene Expression
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Humans
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MAP Kinase Kinase 1 / metabolism*
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MAP Kinase Kinase 2 / metabolism*
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MAP Kinase Signaling System
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Nitriles / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Polymerase Chain Reaction
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Pyrimidines / pharmacology
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction*
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Thrombospondin 1 / metabolism*
Substances
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Angiogenesis Modulating Agents
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Butadienes
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Chromones
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Enzyme Inhibitors
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Morpholines
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Nitriles
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PD 173074
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Pyrimidines
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Recombinant Proteins
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Thrombospondin 1
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U 0126
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Fibroblast Growth Factor 8
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Phosphatidylinositol 3-Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Map2k2 protein, mouse