Novel Inhibitors of FGF Signal transduction in Breast Cancer: Targeting the FGFR Adapter Protein SNT-1

摘要

FGF stimulation leads to tyrosine phosphorylation of the protein SNT- 1, which binds to activated FGF receptors. The objective of this work was to determine if SNT-1 protein had a central role in transducing the signals that lead to FGF-mediated antiestrogen resistant growth. We expressed an SNT-1 PTB domain in MCF-7 cells using a modified tetracycline inducible expression system. Upon induction of the PTB domain, we observed a significant decrease of FGF- dependent tyrosine phosphorylation of wild type SNT-1, strong inhibition of complex formation between SNT-1, Gab-1 and Sos-1, blocked activation of Ras as well as phosphorylation of MAP kinase indicating that the SNT-1 PTB domain was functioning in a dominant negative manner. Under the same conditions we did not observe a decrease in phosphorylation of AKT and Thr 389 of p70S6K, components of PI-3 kinase pathway. FGF dependent colony formation of MCF-7 cells in media containing the antiestrogen ICI 182,780 was inhibited upon induction of SNT-1 PTB domain. We conclude that SNT-1 plays a major role in the FGF-dependent activation of Ras/MAPK pathway and proliferation of MCF-7 cells and that overexpression of SNT-1 PTB domain can block these responses. We also suggest some SNT-1 independent mechanisms of PI- 3K activation by FGF.