oblast Growth Factor Receptor 4 Regulates Tumor sion by Coupling Fibroblast Growth Factor Signaling to

nloaded rrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression trix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix oproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk varoth FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types includeast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor on front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured te carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with ancer prognosis, increased MT1-MMP–dependent collagen invasion. In this experimental model, knockof FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. as coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and ssion of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP t and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, down of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo ithin three-dimensional collagen. These results will help to explain the reported association of the and w FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors. Cancer Res; 70(20); 7851–61. ©2010 AACR.