The Hippo Pathway in Prostate Gland Homeostasis and Prostate Cancer

描述(申请人提供)：染色体重组导致强启动子和ETS家族转录因子ERG之间的基因融合是人类前列腺癌最常见的遗传事件。ERG过表达的意义和机制尚不清楚。本申请旨在回答这些问题，并建立在我们实验室产生的大量初步证据的基础上。我们产生了转基因小鼠，在小鼠前列腺上皮细胞中过度表达ERG，水平与人类前列腺癌的ERG水平相似，并发现这些动物患上了与年龄相关的前列腺癌。这是令人兴奋的，因为年龄是人类前列腺癌发展中最重要的因素。对ERG转基因动物的分析表明，受河马信号通路负调控的基因具有特异性激活。已知河马途径限制干细胞和祖细胞的自我更新，而河马途径的结构性失活与肝、皮肤、肠和乳腺上皮的癌症有关。HIPPO通路在前列腺上皮和前列腺癌中的意义目前尚不清楚。我们证实了在人前列腺上皮细胞中河马基因的ERG依赖的激活，并发现ERG与河马转录共激活因子YAP1/TAZ结合并增强其转录活性。因此，这一应用的中心假设是，Hippo途径在调节正常前列腺的动态平衡中起重要作用，而Hippo靶基因的激活是前列腺癌中ERG致癌功能的主要途径。我们建议使用体外和体内方法来全面研究这一假说。在目标1中，我们将研究ERG和YAP1/TAZ蛋白之间的物理和功能联系。在目标2中，我们将确定ERG对河马途径转录输出的机制和影响。在目标3中，我们将使用基因工程小鼠来揭示河马通路在正常前列腺动态平衡和ERG介导的前列腺癌中的重要性。总体而言，这项研究将确定河马途径在正常前列腺中的作用，并揭示导致前列腺癌发展的关键机制。

DESCRIPTION (provided by applicant): Chromosomal recombination resulting in a gene fusion between a strong promoter and an ETS- family transcription factor ERG is the most common genetic event in human prostate cancer. The significance of ERG overexpression and the mechanisms of ERG are not well understood. This application aims at answering these questions and builds on extensive preliminary evidence generated in our laboratory. We generated transgenic mice overexpressing ERG in mouse prostate epithelium at the levels similar to the levels of ERG in human prostate cancer, and found that these animals develop age-related prostate cancer. This is exciting, because age is the most significant factor in development of human prostate cancer. The analyses of ERG transgenic animals revealed specific activation of the genes negatively controlled by the Hippo signaling pathway. Hippo pathway is known to restrict self-renewal of stem and progenitor cells and constitutive inactivation of the Hippo pathway is causally involved in cancer in liver, skin, intestine and breast epithelium. The significance of the Hippo pathway in prostate epithelium and prostate cancer is presently unknown. We confirmed ERG-dependent activation of Hippo genes in human prostate epithelial cells and found that ERG binds to Hippo transcriptional co-activators YAP1/TAZ and potentiates their transcriptional activity. Thus, the central hypothesis of this application is that the Hippo pathway plays an important role in regulation of homeostasis of normal prostate gland and activation of Hippo target genes is the primary pathway responsible for oncogenic function of ERG in prostate cancer. We propose to comprehensively investigate this hypothesis using in vitro and in vivo approaches. In aim 1, we will investigate the physical and functional connection between ERG and YAP1/TAZ proteins. In aim 2, we will determine the mechanisms and the impact of ERG on the transcriptional output of the Hippo pathway. In aim 3, we will use genetically engineered mice to reveal the significance of the Hippo pathway in normal prostate gland homeostasis and ERG- mediated prostate cancer. Overall, this study will determine the role of the Hippo pathway in normal prostate and reveal the pivotal mechanisms responsible for the development of prostate cancer.