Genetic Analysis of a Prostate Tumor Suppressor Region

描述（由申请人提供）：我们已发表的和初步的研究表明，小鼠精囊形状（svs）突变导致前列腺分支形态发生和大小缺陷，以及对激素诱导的病变（类似于早期前列腺癌）的敏感性增加。这些数据表明，svs突变可以作为一个独特的切入点，以确定一个遗传途径，调节前列腺的分支形态发生和肿瘤抑制。我们已经确定了一个候选的Svs突变的Fgfr 2基因，这是与Fgfr 2转录的选择性剪接的变化，并在下游信号转导通路的激活的变化。Fgfr 2先前已被证明具有肿瘤抑制活性前列腺癌细胞系，但人类前列腺癌的研究报告了Fgfr 2的相互矛盾的结果。我们对svs突变小鼠的研究为以前研究中的矛盾提供了一个可能的解释。我们已经证明，前列腺和精囊中Fgfr 2的选择性剪接比以前认识到的要复杂得多，并且选择性剪接的Fgfr 2亚型谱的变化而不改变蛋白水平（如在svs小鼠中）可以对前列腺发育和癌症易感性产生深远的影响。本提案中概述的实验将探索Fgfr 2选择性剪接在前列腺发育和癌症进展中的作用。目的1中的实验将测试svs突变是否与Fgfr 2等位。目的2和3中的实验将检验Fgfr 2选择性剪接的变化可促进小鼠和人类前列腺癌进展的假设。目的4中的实验将鉴定与前列腺中Fgfr 2的存在/不存在和可变剪接相关的基因表达变化。这些实验将确定促进小鼠和人类前列腺癌进展的Fgfr 2突变类型（同种型转换与缺失）。他们还将定义Fgfr 2用于协调前列腺中分支形态发生和肿瘤抑制的机制。

DESCRIPTION (provided by applicant): 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.