Examination of the Role of DNA Methylation Changes in Prostate Cancer using the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Model
Abstract
We have previously shown that Transgenic Adenocarcinoma of Mouse Prostate (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. In addition, we have identified several genes (Gsts, Mgmt, Pdlim4, and Zfp185), that are commonly silenced by promoter hypermethylation in human prostate cancer, that are also downregulated in TRAMP tumors. However, in TRAMP these genes do not display promoter hypermethylation. Although further studies suggest that other epigenetic mechanisms may be playing a role in the transcriptional regulation of these genes. Using a TRAMP Dnmt1 hypomorphic mouse model, we have tested the role of Dnmt1 in prostate cancer progression. At an early time point hypomorphic mice display advanced tumor progression and at a later time point hypomorphic mice have repressed tumor progression and metastases. These results suggest that both global hypomethylation and locus specific hypermethylation are important events during TRAMP tumorigenesis. This indicates a dual role for Dnmt1 in TRAMP tumor progression with a suppressive role in early stage disease and oncogenic role at later stages.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2009
- Accession Number
- ADA502739
Entities
People
- Shannon R. Kinney
Organizations
- Roswell Park Comprehensive Cancer Center