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: 9265055
• 负责人: Scott D Cramer
• 金额: $ 34.19万
• 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/9265055
• 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; 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; 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; outcome prediction; prognostic; prognostic value; prostate cancer model; protein expression; public health relevance; 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）：前列腺癌的特征是大量基因组重排和缺失。我们发现，ERG 易位阴性前列腺癌中基因 CHD1 和 MAP3K7 共同缺失。为了证明功能协同性，我们使用了一种新型小鼠前列腺干细胞发育模型，结果表明，CHD1 和 MAP3K7 的协同缺失会促进侵袭性前列腺癌表型，具有谱系分化改变、分泌产物异常、大量核异型性、E-钙粘蛋白缺失以及神经元和神经内分泌标记物富集。还观察到 AR 表达的显着变化。使用 LNCaP 模型，我们还证明 CHD1 和 MAP3K7 的缺失会促进去势抵抗性前列腺癌。其他拷贝数改变与侵袭性 CHD1/MAP3K7 无效表型的功能相互作用将在目标 1 中进行探讨。目标 2 将定义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来检测临床样本中蛋白质表达的丧失。在目标 3 中，我们将评估一组具有稳健临床结果的独特男性前列腺组织中免疫组织化学的预后价值。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。 CHD1 和 MAP3K7 的共同缺失发生在 10-15% 的原发性肿瘤中。大约 50% 的共缺失患者会出现复发。如果这些缺失发生在原发性肿瘤中并预测生存率较差，则可以根据 MA​​P3K7 和 CHD1 状态对男性进行分层。对前列腺癌这种变异的功能性理解可能会在未来带来新的治疗靶向策略。