Alternative splicing of fibroblast growth factor receptors in human prostate cancer

BACKGROUND. Fibroblast growth factors (FGFs) are known to play an important role in the growth of normal prostatic epithelial cells and may promote pr oliferation of neoplastic prostatic epithelial cells via autocrine or parac rine mechanisms. The affinity of FCFs for FGF receptors 1-3 is critically d ependent on an alternative splicing event involving the coding region for t he carboxy terminal portion of the third extracellular immunoglobulin-like domain that leads to two different isoforms of each receptor (IIIb and IIIc ). We therefore sought to determine whether changes in alternative splicing of FGF receptors occur in human prostate cancer. METHODS. RNAs from normal prostate and clinically localized or metastatic p rostate cancers were analyzed by reverse transcriptase polymerase chain rea ction (RT-PCR) followed by digestion of products with restriction enzymes s pecific for each FGF receptor isoform and quantitation of the relative amou nts of each isoform after electrophoresis. For FGFR-2, this was correlated with immunohistochemistry to determine the localization of the protein prod uct. RESULTS. FGFR-1 is expressed exclusively as the IIIc isoform in prostate ca ncer while FCFR-3 is expressed predominantly as the IIIb isoform, similar t o the expression pattern in normal prostatic epithelial cells. In contrast, there was variable expression of the FGFR-2 IIIb and IIIc isoforms. In the majority of cases the FGFR-2 IIIb isoform was the predominant or exclusive isoform expressed, similar to normal epithelial cells, but in a subset of cases the IIIc isoform was increased, indicating a change in alternative sp licing of FGFR-2 in some cases. CONCLUSIONS. In most cases of prostate cancer there are no changes in alter native splicing of FGF receptors, but in a subgroup there is increased expr ession of the FGFR-2 IIIc isoform. Given that the affinity of FGFs is highl y dependent on the isoform of FGF receptor expressed, this information is c ritical in understanding the effects of FGFs on prostate cancer cells in vi vo. Prostate 46:163-172, 2001. (C) 2001 Wiley-Liss, Inc.