Functions in tumors of recurrently amplified Prefoldin-4

描述（由申请人提供）：该项目将基于一组挑衅性的初步结果解决一个假设，即前折叠蛋白-4（前折叠蛋白前伴侣蛋白复合物的一种组分）在肿瘤中被基因拷贝数增加上调时作为主要的肿瘤进展因子。来自人类癌症小鼠模型和人类肿瘤中PFDN-4表达谱的生物信息学评估的新结果表明，PFDN-4是一种基因，其上调功能有助于肿瘤进展。这一假说为在乳腺癌、卵巢癌和其他人类肿瘤中检测到的人类染色体20 q13的复发性染色体扩增，以及胰腺神经内分泌癌和乳腺癌小鼠模型中同线染色体位点的获得提供了理论依据。具体目标是： 1.阐明与上调前折叠蛋白-4相关的致癌活性的机制基础，特别是评估其转化作用与其作为调节肌动蛋白和微管蛋白生物合成的前折叠蛋白前伴侣蛋白复合物的正常功能相关的可能性。 2.评估前折叠蛋白-4上调在胰岛和乳腺多阶段癌变小鼠模型中的因果关系和作用。 3.研究PFDN-4上调在人类肿瘤病变阶段的模式和相关性，所述人类肿瘤倾向于Chr_20q13基因座的DNA拷贝数增加，特别是评估PFDN-4的拷贝和表达增加将与恶性程度增加的区域相关的含义，支持这一假设，即前折叠蛋白-4是一种肿瘤进展因子，其上调是人类癌症中20 q13基因座复发性扩增的基础。 如果即将到来的数据证实了这一假设，并澄清了PFDN-4在多步骤肿瘤发生过程中何时以及如何发挥其致癌作用，那么前折叠蛋白活性和/或前折叠蛋白-4亚基很可能成为开发寻求下调活性的药理学抑制剂的靶标，特别是在Chr_20q13扩增和PFDN-4上调的肿瘤癌症中，就像赫赛汀在乳腺癌中靶向Her 2/Neu一样，其中Her 2/Neu上调。

DESCRIPTION (provided by applicant): This project will address a hypothesis, based on a provocative set of preliminary results, that Prefoldin-4, a component of the Prefoldin pre-chaperonin complex, acts as a dominant tumor progression factor when upregulated by gene copy number increases in tumors. The new results, both from a mouse model of human cancer, and from bioinformatic assessment of PFDN-4 expression profiles in human tumors, implicates PFDN-4 as a gene whose upregulation functionally contributes to tumor progression. The hypothesis presents a rationale for the recurrent chromosomal amplification of human chromosome 20q13 detected in a significant fraction of breast, ovarian, and other human tumors, and for gains of the syntenic chromosomal locus in mouse models of pancreatic neuroendocrine and breast cancer. The specific aims are to: 1. Elucidate the mechanistic basis for the oncogenic activity associated with upregulated Prefoldin-4, assessing in particular the possibility that its transforming action is related to its normal function as a component of the Prefoldin prechaperonin complex that modulates actin and tubulin biosynthesis. 2. Assess the causality and roles of Prefoldin-4 upregulation in mouse models of multistage carcinogenesis, of pancreatic islets and breast. 3. Investigate the patterns and association of PFDN-4 upregulation in lesional stages of human tumors prone to DNA copy number increases of the Chr_20q13 locus, assessing in particular the implication that increased copy and expression of PFDN-4 will correlate with regions of increased malignancy, in support of the hypothesis that Prefoldin-4 is a tumor progression factor whose upregulation underlies the recurrent amplification of the 20q13 locus in human cancers. If the data forthcoming substantiate the hypothesis, and clarify when and how PFDN-4 exerts its oncogenic effects in the course of multi-step tumorigenesis, Prefoldin activity and/or the Prefoldin-4 subunit may well become the target for development of pharmacological inhibitors seeking to down-modulate activity, in particular in tumors cancers where Chr_20q13 is amplified and PFDN-4 upregulated, much as for Herceptin targeting of Her2/Neu in those breast cancers where it is upregulated.