Novel prostate cancer oncogenes identified by transposon mutagenesis

摘要 我们已经进行了两个物种的初步筛选，以发现新的癌基因和肿瘤 抑制基因可推动小鼠前列腺癌的启动和/或进展 人类。以转座子为基础的小鼠插入突变的初步筛选 建立前列腺癌遗传异质性的模型，并进行全基因组筛查 癌基因和肿瘤抑制基因。二次筛查使用的是人类前列腺癌 通过检测患者样本来验证新候选癌症基因的相关性 人类前列腺癌基因表达改变的同源基因。此屏幕 确定了几个新的前列腺癌候选癌基因和肿瘤抑制基因。 在小鼠屏幕上发现的最早的基因之一，PDE4D，也在 人类前列腺癌患者样本。此外，PDE4D基因的敲除降低了 人前列腺癌细胞的体外和体内增殖。这项提案将调查 前列腺癌新候选癌基因和肿瘤抑制基因 在我们的屏幕中确定，特别强调评估PDE4D作为 前列腺癌候选癌基因和前列腺癌的潜在药物靶点。实验 在该提案的目标1和2中，将模拟PDE4D在正常前列腺和 探讨PDE4D在前列腺中的作用机制。AIM 3的实验将测试NVP- 一种PDE4D选择性小分子抑制剂ABE171，作为一种潜在的抗前列腺癌药物 临床前模型的背景。Aim 4中的实验将评估PDE4D的表达 和其他在我们的初步研究中发现的前列腺癌新候选基因 前列腺癌不同病理分级的表达变化 和/或可预测患者长期预后的表达。总的来说，这些研究 将有助于更好地理解导致前列腺癌的基因多样性途径 进展，他们将确定PDE4D作为前列腺癌新药靶点的适宜性 癌症。

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.