Our published and preliminary studies have shown that the mouse seminal vesicle shape (svs) mutation causes prostatic branching morphogenesis and size defects as well as increased sensitivity to hormone- induced lesions that resemble early stage prostate cancer. These data suggest that the svs mutation can be used as a unique entry-point to identify a genetic pathway that regulates branching morphogenesis and tumor suppression in the prostate. We have identified a candidate svs mutation in the Fgfr2 gene that is associated with changes in alternative splicing of the Fgfr2 transcript, and changes in the activation of downstream signal transduction pathways. Fgfr2 has previously been shown to have tumor suppressor activity prostate cancer cell lines, but studies of human prostate cancer have reported conflicting results for Fgfr2. Our investigation of svs mutant mice suggests a possible explanation for the conflicts among previous studies. We have shown that alternative splicing of Fgfr2 in the prostate and seminal vesicles is much more complex than previously recognized, and changes in the spectrum of alternatively spliced Fgfr2 isoforms without changes in protein levels (as in svs mice) can have a profound impact on prostate development and cancer susceptibility. Experiments outlined in this proposal will explore the role of Fgfr2 alternative splicing in prostatic development and cancer progression. Experiments in Aim 1 will test whether the svs mutation is allelic with Fgfr2. Experiments in Aims 2 and 3 will test the hypothesis that changes in Fgfr2 alternative splicing can contribute to prostate cancer progression in mice and humans. Experiments in Aim 4 will identify gene expression changes associated with the presence/absence and alternative splicing of Fgfr2 in the prostate. These experiments will define the types of Fgfr2 mutation (isoform switching vs. loss) that promote prostate cancer progression in mice and humans. They will also define the mechanisms used by Fgfr2 to coordinate branching morphogenesis and tumor suppression in the prostate. ? ? ?
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