Novel prostate cancer oncogenes identified by transposon mutagenesis

摘要 我们已经进行了两个物种的试点筛选，以发现新的癌基因和肿瘤 可驱动小鼠前列腺癌起始和/或进展的抑制基因， 人类初步筛选利用小鼠中基于转座子的插入诱变， 建立前列腺癌的遗传异质性模型， 癌基因和肿瘤抑制基因。第二次筛查使用人类前列腺癌 患者样本，以通过检查新的候选癌症基因的相关性， 用于在人前列腺癌中改变表达的基因的人直系同源物。此屏幕 鉴定了几个新的候选前列腺癌癌基因和肿瘤抑制基因。 在小鼠筛选中鉴定的第一个基因之一PDE 4D也在小鼠中过表达。 人前列腺癌患者样品。此外，PDE 4D的敲低降低了 体外和体内人前列腺癌细胞的增殖。该提案将调查 新的候选前列腺癌癌基因和肿瘤抑制基因， 在我们的筛选中确定，特别强调评估PDE 4D作为 候选前列腺癌癌基因和前列腺癌中潜在的药物靶点。实验 在该提案的目的1和2中，将模拟正常前列腺中的PDE 4D过表达， 研究PDE 4D在前列腺中的作用机制。目标3中的实验将测试NVP- ABE 171，一种PDE 4D选择性小分子抑制剂，作为一种潜在的抗前列腺癌药物， 临床前模型的背景。目的4中的实验将评估PDE 4D的表达 和其他新的候选前列腺癌基因在我们的初步研究中确定， 不同病理分级前列腺癌组织中表达的变化 和/或预测长期患者结果的表达。总的来说，这些研究 将有助于更好地了解导致前列腺癌的遗传多样性途径 进展，他们将确定PDE 4D作为前列腺新药靶点的适用性 癌

Abstract We have conducted a two-species pilot screen to discover new oncogenes and tumor suppressor genes that can drive prostate cancer initiation and/or progression in mice and humans. The primary screen utilized transposon-based insertional mutagenesis in mice to model genetic heterogeneity in prostate cancer and conduct a genome-wide screen for new oncogenes and tumor suppressor genes. The secondary screen used human prostate cancer patient samples to validate the relevance of novel candidate cancer genes by examining the human orthologs of the genes for altered expression in human prostate cancers. This screen identified several novel candidate prostate cancer oncogenes and tumor suppressor genes. One of the first genes identified in the mouse screen, PDE4D, was also over-expressed in human prostate cancer patient samples. Furthermore, knockdown of PDE4D reduced the proliferation of human prostate cancer cells in vitro and in vivo. This proposal will investigate the novel candidate prostate cancer oncogenes and tumor suppressor genes that have been identified in our screen with a particular emphasis on evaluating the roles of PDE4D as a candidate prostate cancer oncogene and potential drug target in prostate cancer. Experiments in Aims 1 and 2 of the proposal will model PDE4D over-expression in the normal prostate and investigate the mechanism of PDE4D action in the prostate. Experiments in Aim 3 will test NVP- ABE171, a PDE4D-selective small molecule inhibitor, as a potential anti-prostate cancer drug in the context of pre-clinical models. Experiments in Aim 4 will evaluate the expression of PDE4D and other novel candidate prostate cancer genes identified in our preliminary studies for expression changes associated with different pathologic grades of human prostate cancer and/or expression that is predictive of long-term patient outcomes. Collectively, these studies will lead to a better understanding of the genetically diverse pathways that drive prostate cancer progression, and they will determine the suitability of PDE4D as a new drug target in prostate cancer.