Functions in tumors of recurrently amplified Prefoldin-4

描述(由申请人提供)：这个项目将解决一个假设，基于一组具有挑衅性的初步结果，即前折叠蛋白-4，前折叠蛋白前伴侣复合体的一种成分，在肿瘤中因基因拷贝数增加而上调时，作为主导的肿瘤进展因子。这一新的结果，既来自人类癌症的小鼠模型，也来自对人类肿瘤中PFDN-4表达谱的生物信息学评估，暗示PFDN-4是一种其上调功能有助于肿瘤进展的基因。这一假说为在乳腺、卵巢和其他人类肿瘤的相当大一部分中检测到人类染色体20q13的反复染色体扩增，以及在胰腺神经内分泌和乳腺癌的小鼠模型中获得同线染色体位点提供了理论基础。具体目标是： 1.阐明与上调的前折叠蛋白-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体的正常功能有关的可能性。 2.评价Prefoldin-4在小鼠多阶段癌变、胰岛和乳腺癌变过程中的作用及因果关系。 3.研究PFDN-4在易发生Chr_20q13基因座DNA拷贝数增加的人类肿瘤病变阶段中上调的模式及其相关性，特别是评估PFDN-4的复制和表达增加将与恶性程度增加的区域相关的含义，支持前折叠蛋白-4是一种肿瘤进展因子的假设，其上调是20q13基因座在人类癌症中反复扩增的基础。 如果即将公布的数据证实了这一假说，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致癌作用，前折叠蛋白活性和/或前折叠蛋白-4亚单位很可能成为寻求下调活性的药物抑制剂开发的靶点，特别是在Chr_20q13扩增和PFDN-4上调的肿瘤中，就像在Herceptin靶向Her2/Neu上调的乳腺癌中一样。

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.