CHD1 and MAP3K7 coordinate deletion in aggressive ERG translocation negative prostate cancer

CHD1 和 MAP3K7 在侵袭性 ERG 易位阴性前列腺癌中协调缺失

• 批准号: 9090060
• 负责人: Scott D Cramer
• 金额: $ 38.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090060
• 关键词: Androgen Receptor; Androgens; Animal Model; Binding; Biochemical; CHD1 gene; Castration; Cells; Cessation of life; ChIP-seq; Clinical; Complex; Custom; DNA Sequence Rearrangement; Development; Differentiation Antigens; Disease; E-Cadherin; Eph Family Receptors; Ephrins; Epigenetic Process; Future; Genes; Genomic approach; Genomics; Growth; Health; Histones; Human; Immunohistochemistry; In Vitro; Kidney; LNCaP; Lead; Libraries; Ligands; MAP Kinase Kinase Kinase; MAP3K7 gene; Malignant neoplasm of prostate; Mediator of activation protein; Modeling; Mus; Mutation; Neoplasm Metastasis; Neurons; Neurosecretory Systems; Nuclear Atypia; Outcome; Pathology; Pathway interactions; Patients; Pattern; Phenocopy; Phenotype; Primary Neoplasm; Prostate; Prostatectomy; Proteins; Reading; Receptor Protein-Tyrosine Kinases; Recurrence; Relapse; Resistance; Risk; Role; Sampling; Signal Transduction; Specimen; Stem cells; Techniques; Tissue Recombination; Tissues; Tumorigenicity; Universities; Up-Regulation; Variant; Work; base; biological adaptation to stress; cancer cell; cohort; cytokine; functional genomics; genetic manipulation; human disease; in vivo; men; new therapeutic target; novel; prognostic; prognostic value; prostate cancer model; protein expression; small hairpin RNA; statistics; transcriptome sequencing; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Prostate cancer is characterized by large genomic rearrangements and deletions. We show that the genes CHD1 and MAP3K7 are co-deleted in ERG translocation negative prostate cancer. To demonstrate a functional cooperativity we used a novel mouse prostate stem cell developmental model and showed that collaborative loss of CHD1 and MAP3K7 promotes an aggressive prostate cancer phenotype with altered lineage differentiation, abnormal secretory products, massive nuclear atypia, loss of E-cadherin and enrichment in neuronal and neuroendocrine markers. Profound alterations in AR expression were also observed. Using a LNCaP model we also demonstrate that loss of CHD1 and MAP3K7 promotes castrate-resistant prostate cancer. The functional interactions of other copy number alterations with the aggressive CHD1/MAP3K7 null phenotype will be explored in Aim 1. Aim 2 will define the functional roles of androgen receptor variants and downstream targets in a castration model of prostate cancer and identify novel mediators of aggressive growth. We have validated immunohistochemical techniques to detect loss of protein expression in clinical specimens. In Aim 3 we will assess the prognostic value of immunohistochemistry in prostate tissue from a unique cohort of men with robust clinical outcomes. This work could have impact on the management of the most aggressive prostate cancer. Co-deletion of CHD1 and MAP3K7 occurs in 10-15 % of primary tumors. Relapse occurs in approximately 50% of patients with co-deletion. If these deletions occur in primary tumors and predict poor survival, men could be stratified based on MAP3K7 and CHD1 status. A functional understanding of this variant of prostate cancer could lead to novel therapeutic targeting strategies in the future.

 描述（由适用提供）：前列腺癌的特征是大型基因组重排和缺失。我们表明，基因CHD1和MAP3K7在ERG易位前列腺癌中被共删除。为了证明功能协调，我们使用了一种新型的小鼠前列腺干细胞发育模型，并表明CHD1和MAP3K7的协作丧失促进了一种积极的前列腺癌表型，随着谱系分化的改变，异常的秘密产物，巨大的核核病患者，E-cadherin，E-Cadherin，E-Cadherin和Neuronal和Neuroonal和Neuroonal和Neuroonal和Neuroendocrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrecrains a。还观察到AR表达的深刻改变。使用LNCAP模型，我们还证明了CHD1和MAP3K7的丧失会促进耐Castrate的前列腺癌。在AIM 1中将探索其他拷贝数变化与侵略性CHD1/MAP3K7无效表型的功能相互作用。AIM2将在前列腺癌的cast割模型中定义雄激素受体变体和下游靶标的功能作用，并识别出侵略性生长的新型介体。我们已经验证了免疫组织化学技术，以检测临床规范中蛋白质表达的丧失。在AIM 3中，我们将评估来自具有强大临床结果的独特男性队列中前列腺组织中免疫组织化学的前列腺价值。这项工作可能会影响最激进的前列腺癌的管理。 CHD1和MAP3K7的共同删除发生在10-15％的原发性肿瘤中。大约50％的共同缺失患者发生复发。如果这些缺失发生在原发性肿瘤中并预测生存率不佳，则可以根据MAP3K7和CHD1状态对男性进行分层。对这种前列腺癌变体的功能理解可能会导致新的治疗靶向策略。