Genetic Analysis of a Prostate Tumor Suppressor Region

描述（由申请人提供）：我们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，以及对类似于早期前列腺癌的激素诱导病变的敏感性增加。这些数据表明，svs突变可以作为一个独特的切入点，以确定调控前列腺分支形态发生和肿瘤抑制的遗传途径。我们已经在Fgfr2基因中发现了一个候选的svs突变，该突变与Fgfr2转录物选择性剪接的变化以及下游信号转导途径激活的变化有关。Fgfr2先前已被证明具有前列腺癌细胞系的肿瘤抑制活性，但对人类前列腺癌的研究报告了与Fgfr2相矛盾的结果。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，Fgfr2在前列腺和精囊中的选择性剪接比以前认识到的要复杂得多，而Fgfr2选择性剪接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Fgfr2选择性剪接在前列腺发育和癌症进展中的作用。Aim 1的实验将测试svs突变是否与Fgfr2等位。目标2和目标3中的实验将验证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的实验将确定与Fgfr2在前列腺中的存在/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（同种异构体转换与缺失）。他们还将确定Fgfr2用于协调前列腺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.