Androgen Signaling in CaP with loss of MAP3K7 and CHD1

前列腺癌的特征是大量的基因组重排和缺失。我们证明了这些基因 在ERG易位阴性前列腺癌中，CHD1和MAP3K7共缺失。要演示 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 CHD1和MAP3K7协同缺失促进侵袭性前列腺癌表型改变 谱系分化，异常分泌产物，大量核异型性，E-钙粘素和 神经和神经内分泌标志物的丰富。AR表达的深刻变化也是 观察到的。使用多个人类细胞系模型，我们还证明了CHD1和MAP3K7的缺失 促进抗去势前列腺癌。该项目将评估AR的下游目标在 应用功能基因组学方法研究MAP3K7和CHD1缺失的肿瘤 这些指标对患者预后的临床影响。这项工作可能会对 最具侵袭性的前列腺癌。CHD1和MAP3K7的共同缺失发生在10%-15%的原发肿瘤中。 大约50%的共缺失患者会复发。如果这些缺失发生在原发肿瘤中 并预测生存不良，男性可以根据MAP3K7和CHD1状态进行分层。功能界别 对前列腺癌这种变种的了解可能会在未来导致新的治疗靶向策略。

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 multiple human cell line models we also demonstrate that loss of CHD1 and MAP3K7 promotes castrate-resistant prostate cancer. This project will evaluate downstream targets of AR altered in tumors with loss of MAP3K7 and CHD1 using functional genomics in vitro and in animal models and assess the clinical impact of these targets on patient outcome. 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.