): A critical event in the progression of prostate cancer is the transition from androgen sensitive tumors to more aggressive, androgen insensitive tumors whose emergence usually presages rapid clinical deterioration and death. A change in the alternative splicing pattern of the fibroblast growth factor receptor 2 (FGF-R2) has been shown to accompany this transition in a rat model of prostate cancer. This change in the expressed FGF-R2 isoform produces a receptor which does not respond to FGF-7, which normally plays a role in maintaining terminal differentiation of prostatic epithelial cells. The investigators have extended this observation to two human prostate tumors, DUKAP-1 and DU9479, which are maintained as xenografts in nude mice and demonstrate androgen sensitivity and insensitivity, respectively. This loss of responsiveness to FGF-7 as a result of alternative splicing in androgen insensitive tumors in both rats and humans suggests that this event may be important in permitting the development of autocrine ligand-receptor loops leading to autonomous growth and greater malignancy. The sponsor of the proposed project and the laboratory have extensive experience investigating RNA splicing, which is conducive to accomplishing the scientific goals outlined here as well as facilitating the development of the candidate into a productive independent investigator. The candidate views study of splicing mechanisms which impact on cancer progression as an excellent area in which to develop the skills which will allow him to extend his expertise into additional research areas. This proposal pursues two primary aims. First, the mechanisms controlling the alternative splicing of the FGF-R2 receptor will be investigated using biochemical techniques, with a goal being to identify novel or known factors which govern this mutually elusive splicing event. Second, additional human prostate tumor specimens will be analyzed to see if this change in alternative splicing may serve as a general marker of androgen insensitivity and an increased propensity towards aggressive growth and metastasis.
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| Carstens, R P; Wagner, E J; Garcia-Blanco, M A (2000) An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein. Mol Cell Biol 20:7388-400 |
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