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（由申请人提供）：前列腺癌的特征在于大的基因组重排和缺失。我们发现在ERG易位阴性的前列腺癌中CHD 1和MAP 3 K7基因共缺失。为了证明功能协同性，我们使用了一种新的小鼠前列腺干细胞发育模型，并表明CHD 1和MAP 3 K7的协同丢失促进了具有改变的谱系分化、异常分泌产物、大量核内分泌、E-钙粘蛋白丢失以及神经元和神经内分泌标志物富集的侵袭性前列腺癌表型。还观察到AR表达的显著变化。使用LNCaP模型，我们还证明了CHD 1和MAP 3 K7的缺失促进去势抵抗性前列腺癌。其他拷贝数改变与侵袭性CHD 1/MAP 3 K7无效表型的功能相互作用将在目标1中探索。目的2将确定雄激素受体变异体和下游靶点在前列腺癌去势模型中的功能作用，并确定侵袭性生长的新介质。我们已经验证了免疫组织化学技术，以检测临床标本中蛋白质表达的损失。在目标3中，我们将评估免疫组化在前列腺组织中的预后价值，这些前列腺组织来自一个独特的具有稳健临床结局的男性队列。这项工作可能会对最具侵袭性的前列腺癌的治疗产生影响。CHD 1和MAP 3 K7的共缺失发生在10- 15%的原发性肿瘤中。复发发生在大约50%的共缺失患者中。如果这些缺失发生在原发性肿瘤中并预测生存率低，则可以根据MAP 3 K7和CHD 1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在未来产生新的治疗靶向策略。