FGFR-4 Arg388 Enhances Prostate Cancer Progression via Extracellular Signal-Related Kinase and Serum Response Factor Signaling

Purpose: Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg(388)) instead of glycine (Gly(388)), is associated with aggressive disease. The FGFR-4 Arg(388) variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly(388). However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Experimental Design: Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg(388) or Gly(388) was used to establish a gene signature associated with FGFR-4 Arg(388) expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg(388) expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Results: Expression of the FGFR-4 Arg(388) protein leads to increased activity of the extracellular signal-related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg(388) in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. Conclusions: These studies define a signal transduction pathway downstream of FGFR-4 Arg(388) that acts via ERK and SRF to promote PCa progression. Clin Cancer Res; 17(13); 4355-66. (C) 2011 AACR.