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

Abstract

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 (Arg³⁸⁸) instead of glycine (Gly³⁸⁸), is associated with aggressive disease. The FGFR-4 Arg³⁸⁸ variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly³⁸⁸. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg³⁸⁸ or Gly³⁸⁸ was used to establish a gene signature associated with FGFR-4 Arg³⁸⁸ expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg³⁸⁸ expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Expression of the FGFR-4 Arg³⁸⁸ 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 Arg³⁸⁸ in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. These studies define a signal transduction pathway downstream of FGFR-4 Arg³⁸⁸ that acts via ERK and SRF to promote PCa progression.