Cell Specific Expression Signatures in Prostate Cancer (RO1 DK065977)

前列腺癌中的细胞特异性表达特征 (RO1 DK065977)

• 批准号: 8304925
• 负责人: SHIV SRIVASTAVA
• 金额: $ 23.4万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304925
• 关键词: Affect; Androgen Receptor; Behavior; Biochemical; Biological; Biological Markers; Biological Process; Biology; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cells; Clinical; Data; Defect; Detection; Development; Diagnosis; Ectopic Expression; Epithelial; Epithelial Cells; Epithelium; Evaluation; Experimental Models; Fingerprint; Foundations; Gene Activation; Gene Expression; Gene Expression Profile; Gene Fusion; Gene Mutation; Genes; Genetic; Gland; Goals; Growth; Human; Invasive Lesion; Laboratories; Length; MSMB gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Modeling; Molecular; Molecular Profiling; Mus; NKX3-1 gene; Nature; Oncogene Proteins; Oncogenes; Oncogenic; PTEN gene; Patients; Prostate; Prostatic; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Research; Resources; Specificity; Specimen; Spliced Genes; Stratification; Stromal Cells; TMPRSS2 gene; Tissues; Transgenic Mice; Translating; Validation; Variant; gene discovery; gene function; insight; knock-down; mouse model; neoplastic cell; next generation; novel; novel therapeutics; outcome forecast; overexpression; prognostic; programs; promoter; reconstitution; therapeutic target; transcription factor; translational study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Our research focus of epithelial and stromal cell specific gene expression signatures of normal and malignant human prostate tissues has led to the development of more precise CaP gene discovery and validation platforms, molecular bio-specimen resources and important new discoveries. Most notable of these promising findings highlighted ETS related gene (ERG) overexpression as a common feature (60-70%) of the epithelial cell transcriptome of prostate cancers. Subsequently ERG was shown to be a common fusion partner in prevalent TMPRSS2 and ETS related gene fusions leading to the overexpression of ERG through the androgen receptor (AR) regulated TMPRSS2 gene promoter in CaP. Accumulating evidence from various experimental models and human prostate cancers from our and other laboratories now generally support causal nature of ERG oncogenic activation in CaP. The central hypothesis of this proposal is that unscheduled androgenic activation of the ERG in prostate is causal in CaP development and/or progression. The goals of the proposal will be achieved by following aims: Aim 1. Development of new insights into mechanisms of ERG activation in CaP. ERG functions will be defined in cell culture and mouse prostate reconstitution models. Effects of ERG knock-down or ectopic expression of the full length TMPRSS2-ERG products commonly detected in CaP will be evaluated for biological features of cell differentiation and mechanism of regulating ERG transcriptional targets: PSA, NKX3.1, MSMB and SLC45A3. Our original information on ERG splice variants in CaP will be translated into a new transgenic mouse model to assess the assess effects of androgenic activation of mouse Erg on prostate differentiation and cancer. Aim 2. Delineation of ERG and C-MYC cooperativity in prostate tumorigenesis. We shall define biologic and biochemical mechanisms of regulation of C-MYC by ERG and cooperative effects of C-MYC and ERG in abrogating prostate epithelial differentiation programs. Mice overexpressing ERG and C-MYC have been generated to evaluate biological effects of these two critical genes in prostate epithelial differentiation and malignancy. Aim 3. New strategies to define clinical utility of the ERG alterations in stratification and prognosis of CaP. We will evaluate the unprecedented specificity of ERG MAb (>99.9%) for detecting ERG positive tumor cells in enhancing CaP diagnosis and assessing biologic behavior of ERG positive CaP. We will evaluate prognostic value of detecting ERG alterations in combination with C-MYC, AR PTEN, and AKT levels in prostate tumors. Significance: New insights into the CaP associated ERG functions and highly specific ERG detection in clinical specimens will provide will break new grounds in developing biologic stratification of CaP and new therapeutic strategies.

描述（由申请人提供）：我们的研究重点是正常和恶性人类前列腺组织的上皮细胞和基质细胞特异性基因表达特征，这导致了更精确的CaP基因发现和验证平台、分子生物样本资源和重要新发现的开发。这些有希望的发现中最值得注意的是，ETS 相关基因 (ERG) 过度表达是前列腺癌上皮细胞转录组的一个共同特征 (60-70%)。随后，ERG 被证明是流行的 TMPRSS2 和 ETS 相关基因融合中的常见融合伴侣，导致 ERG 通过 CaP 中雄激素受体 (AR) 调节的 TMPRSS2 基因启动子过度表达。我们和其他实验室从各种实验模型和人类前列腺癌中积累的证据现在普遍支持 CaP 中 ERG 致癌激活的因果关系。该提议的中心假设是前列腺中 ERG 的非计划雄激素激活是 CaP 发生和/或进展的原因。该提案的目标将通过以下目标来实现： 目标 1. 开发对 CaP 中 ERG 激活机制的新见解。 ERG 功能将在细胞培养和小鼠前列腺重建模型中定义。将评估 CaP 中常见的全长 TMPRSS2-ERG 产物的 ERG 敲低或异位表达的影响，以了解细胞分化的生物学特征和调节 ERG 转录靶点的机制：PSA、NKX3.1、MSMB 和 SLC45A3。我们关于 CaP 中 ERG 剪接变异的原始信息将被转化为新的转基因小鼠模型，以评估小鼠 Erg 雄激素激活对前列腺分化和癌症的影响。目标 2. 描述 ERG 和 C-MYC 在前列腺肿瘤发生中的协同作用。我们将定义 ERG 调节 C-MYC 的生物学和生化机制以及 C-MYC 和 ERG 在废除前列腺上皮分化程序中的协同作用。已经培育出过表达 ERG 和 C-MYC 的小鼠来评估这两个关键基因在前列腺上皮分化和恶性肿瘤中的生物效应。目标 3. 定义 ERG 改变在 CaP 分层和预后中的临床效用的新策略。我们将评估 ERG MAb 在检测 ERG 阳性肿瘤细胞方面前所未有的特异性 (>99.9%)，以增强 CaP 诊断和评估 ERG 阳性 CaP 的生物学行为。我们将评估检测 ERG 变化与前列腺肿瘤中 C-MYC、AR PTEN 和 AKT 水平相结合的预后价值。意义：对 CaP 相关 ERG 功能和临床样本中高度特异性 ERG 检测的新见解将为开发 CaP 生物学分层和新治疗策略开辟新天地。