Fibroblast growth factor 8 induced downregulation of thrombospondin 1 is mediated by the MEK/ERK and PI3K pathways in breast cancer cells.
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.
Tarkkonen
Kati
K
Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, 20520, Turku, Finland. kati.tarkkonen@utu.fi
Ruohola
Johanna
J
Härkönen
Pirkko
P
D043924:Angiogenesis Modulating Agents / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000378:metabolism*
D043924:Angiogenesis Modulating Agents; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; C115711:PD 173074; D011743:Pyrimidines; D011994:Recombinant Proteins; D019700:Thrombospondin 1; C113580:U 0126; D051524:Fibroblast Growth Factor 8; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse