Examination of the Role of DNA Methylation Changes in Prostate Cancer using the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Model

摘要

I have characterized the epigenetic changes that occur throughout tumor progression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse model. In addition, I examined the role of Dnmt1 in normal prostate development and TRAMP tumorigenesis. TRAMP tumors display altered DNA methyltransferase (Dnmt) expression and DNA methylation patterns, such that global DNA hypomethylation occurs early, while locus specific DNA hypermethylation occurs late, during TRAMP tumor progression. We have identified a number of genes that are promoter hypermethylation events in TRAMP tumors. Interestingly, several loci display a unique phenomenon of gene body methylation correlating with increased expression. While Dnmt1 hypomorphic mouse prostates develop normally, decreased Dnmt1 expression in TRAMP mice (TRAMP Dnmt1 hypomorphic mice) leads to advanced tumor progression at early time points and repressed tumor development and metastases at a later time point. These results suggest that both global hypomethylation and locus specific hypermethylation are important events during TRAMP tumorigenesis and that Dnmt1 plays a dual role in TRAMP tumor progression with a suppressive function in early stage disease and oncogenic function at later stages.