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

 描述(申请人提供)：前列腺癌的特点是大的基因组重排和缺失。我们发现在ERG易位阴性前列腺癌中CHD1和MAP3K7基因共缺失。为了证明功能的协同性，我们使用了一个新的小鼠前列腺干细胞发育模型，结果表明，CHD1和MAP3K7的协同缺失促进了侵袭性前列腺癌的表型，表现为谱系分化改变、分泌产物异常、大量核异型性、E-钙粘素丢失以及神经元和神经内分泌标记物的丰富。AR的表达也发生了深刻的变化。使用LNCaP模型，我们还证明了CHD1和MAP3K7的缺失促进了去势抵抗前列腺癌的发生。目标1将探索其他拷贝数改变与侵袭性CHD1/MAP3K7缺失表型的功能相互作用。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标本中蛋白表达的丢失。在目标3中，我们将评估前列腺组织中免疫组织化学的预后价值，这些组织来自一组独特的临床结果良好的男性。这项工作可能会对最具侵袭性的前列腺癌的管理产生影响。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，并预测存活率较低，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了解可能会在未来导致新的治疗靶向策略。

 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.