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.
