The most commonly observed molecular events that correlate with histological changes evident with progression to the malignant state in the prostate are changes in the expression of multiple growth factors and their cognate receptors. Among these events is the observation that there are discernible differences in the fibroblast growth factor receptor (FGFR) is forms expressed in benign and normal prostate epithelial cells versus adenocarcinoma. Specifically, FGFR2, which is associated with homeostasis and differentiation, is replaced in malignant cells by FGFR1 that binds to a broader subset of FGF ligands. By combining a technology for regulating FGFR1 and FGFR2 signaling based on chemically induced dimerization (CID) with the autochthonous TRAMP murine model for prostate cancer, the PI proposes to study the differential roles of FGF receptors in TRAMP-derived prostate epithelial cells both in vitro and in vivo. The PI will: (1) determine whether the cytoplasmic domains of FGFR1 and FGFR2 can trigger qualitatively or quantitatively distinct signaling pathways leading to either proliferation or differentiation in prostate cancer cells, (ii) test the hypothesis that FGFR1 signaling promotes tumor progression while FGFR2 drives differentiation in vivo, and (iii) test the hypothesis that differential signaling by FGFR1 versus FGFR2 leads to the transcriptional induction of unique sets of signaling molecules driving proliferation rather than homeostasis and differentiation.
| Xie, Xiaoming; Luo, Zheng; Slawin, Kevin M et al. (2004) The EZC-prostate model: noninvasive prostate imaging in living mice. Mol Endocrinol 18:722-32 |
| Freeman, Kevin W; Gangula, Rama D; Welm, Bryan E et al. (2003) Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation. Cancer Res 63:6237-43 |
| Freeman, Kevin W; Welm, Bryan E; Gangula, Rama D et al. (2003) Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res 63:8256-63 |
| Li, B; Desai, S A; MacCorkle-Chosnek, R A et al. (2002) A novel conditional Akt 'survival switch' reversibly protects cells from apoptosis. Gene Ther 9:233-44 |
