Defining the Role of ERG in Modulating the AR Cistrome and Antiandrogen Sensitivity

定义 ERG 在调节 AR Cistrome 和抗雄激素敏感性中的作用

• 批准号: 8863630
• 负责人: CHARLES L. SAWYERS
• 金额: $ 48.71万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8863630
• 关键词: Adenocarcinoma; Androgen Antagonists; Androgen Receptor; Androgens; Binding; Binding Sites; Biological Markers; Biology; Bypass; Castration; ChIP-seq; Chromatin; Chromosomal translocation; Clinical; Complex; Data; Disease Progression; Doxycycline; ETV1 gene; ETV4 gene; Epithelial Cells; Epithelium; Event; FLI1 gene; Family; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Human; In Vitro; Knock-in Mouse; Lead; Light; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Abnormality; Mus; Organoids; Output; PTEN gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Population; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Receptor Inhibition; Recurrence; Resistance; Role; Signal Pathway; Signal Transduction; Specimen; System; Systems Biology; TMPRSS2 gene; Technology; Therapeutic; Time; Tissues; Untranslated Regions; Withdrawal; disorder subtype; effective therapy; in vivo; inhibitor/antagonist; innovation; mouse model; next generation; novel; overexpression; prostate cancer model; prostate carcinogenesis; public health relevance; receptor binding; research study; response; targeted treatment; transcription factor; tumor progression; tumorigenesis; validation studies

 DESCRIPTION (provided by applicant): Overexpression of ETS family transcription factors (ERG, ETV1, ETV4, ETV5, FLI1) through genomic fusion is the most common molecular aberration in prostate cancer, occurring in half of all cases. The TMPRSS2-ERG fusion that places ERG under the androgen-regulated TMRPSS2 gene is the predominant fusion, found in 80- 90% of all ETS-positive cancers. The molecular mechanisms underlying ETS-mediated oncogenesis in prostate cancer remain elusive. In genetically engineered mouse models (GEMM), ERG expression alone is not sufficient to drive prostate tumorigenesis. However, it causes dramatic reprogramming of the androgen receptor genomic binding profile (AR cistrome). In conjunction with Pten loss, ERG promotes tumorigenesis as well as significant transcriptome changes and confers resistance to combined PI3K/AR pathway inhibition, a therapy that is highly effective in prostate tumors initiated by Pten loss alone. These findings underscore the important biology that underlies interactions between AR, ERG and PTEN not only in mouse and human prostate cancer models, but also in human prostate cancer clinical specimens where aberrations in these pathways are also highly linked. This R01 project will examine the molecular details underlying these interactions by: (i) determining the mechanisms by which ERG reprograms the AR cistrome, creating a state where the prostate is primed to respond to upstream signals (e.g., Pten loss), (ii) elucidating the signaling events downstream of Pten loss that activate ERG-mediated transcription modules in mouse and human prostate tissue and (iii) determining the impact of ERG on response to AR pathway inhibition. To achieve these Aims, we will make extensive use of new mouse and human prostate organoid technology, generated by our group that enables precise mechanistic analysis of defined populations of luminal and basal prostate epithelial cells in ways not previously possible. We will leverage innovation approached in computational systems biology (Andrea Califano, Columbia) to predict candidate signaling pathways and transcription factors modulated by Pten loss that cooperate with ERG.

 描述（由适用提供）：通过基因组融合的ETS家族转录因子的过表达（ERS，ETV1，ETV4，ETV5，FLI1）是前列腺癌中最常见的分子像差，发生在一半的情况下。将ERG置于雄激素调节的TMRPSS2基因下的TMPRSS2-ERG融合是主要的融合，在所有ETS阳性癌症中的80-90％中发现。 ETS介导的前列腺癌中介导的肿瘤发生的分子机制仍然弹性。在基因工程的小鼠模型（GEMM）中，仅ERG表达不足以驱动前列腺肿瘤发生。但是，它导致雄激素受体基因组结合谱（AR Cistrome）的戏剧性重编程。结合PTEN损失，ERG促进了肿瘤发生以及重大的转录组变化，并赋予对PI3K/AR途径抑制的耐药性，这种疗法对仅PTEN损失引发的前列腺肿瘤非常有效。这些发现强调了重要的生物学，即不仅在小鼠和人类前列腺癌模型中，而且在人类前列腺癌临床标本中，AR，ERG和PTEN之间的相互作用是基础的，在这些途径中也有高度联系。该R01项目将通过以下方式检查这些相互作用的分子细节：（i）确定ERG重新编程的机制，在该机制中，创建了一种状态，在该状态下，在该状态下，将前列腺启动以响应上游信号（例如PTEN损失）（例如，PTEN损失），（II）阐明了PTEN损失的pten损失，并确定了人类偏移的型号，并确定了pten的转化范围，并确定了变性的指示性的涉及老鼠介导的属性，该损失是偏向于介导的，它是指介导的变速器介导的指示性的，并介绍了变性的老鼠介导的（pten）介绍的损失。 ERG对AR途径抑制作用的影响。为了实现这些目标，我们将广泛利用新的小鼠和人类前列腺器官技术，该技术由我们的小组生成，可以通过以前无法以不可能的方式对腔内和基本前列腺上皮细胞的确定种群进行精确的机械分析。我们将 在计算系统生物学（哥伦比亚的安德里亚·加利福尼亚州）中，杠杆创新接近，以预测由PTEN损失与ERG合作调节的候选信号通路和转录因子。