Genetic Analysis of a Prostate Tumor Suppressor Region

描述(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，以及对激素诱导的类似早期前列腺癌的损害的敏感性增加。这些数据表明，SVS突变可以作为一个独特的切入点来识别调节前列腺癌分支形态发生和肿瘤抑制的遗传途径。我们已经确定了FGFR2基因中的一个候选SVS突变，该突变与FGFR2转录本的选择性剪接的变化以及下游信号转导通路的激活变化有关。FGFR2此前已被证明具有肿瘤抑制活性的前列腺癌细胞株，但对人类前列腺癌的研究报告了FGFR2的相互矛盾的结果。我们对SVS突变小鼠的研究为先前研究之间的冲突提供了一个可能的解释。我们已经证明，前列腺和精囊中FGFR2的选择性剪接比之前认识的要复杂得多，并且选择性剪接的FGFR2亚型光谱的变化而不改变蛋白质水平(如在SVS小鼠中)可以对前列腺癌的发育和癌症的易感性产生深远的影响。该提案中概述的实验将探索FGFR2选择性剪接在前列腺发育和癌症进展中的作用。目标1中的实验将测试SVS突变是否与FGFR2等位。AIMS 2和AIMS 3中的实验将测试FGFR2选择性剪接的变化可以促进小鼠和人类前列腺癌进展的假设。AIM 4中的实验将确定与前列腺中FGFR2的存在/缺失和选择性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FGFR2突变类型(同型转换与丢失)。他们还将确定FGFR2用来协调前列腺癌中的分支、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.