Abstract

Three important features of prostate cancer will be addressed in the present proposal that will improve our understanding of risk factors for the development of prostate cancer. These features include: i) the multifocality of prostate cancer which implicates a generalized or field change in cancer susceptibility, ii) the age-dependence of prostate cancer development, and iii) the important role of the Insulin-like Growth Factor Axis in both aging-related and genetic-related cancers. IGF-II is an auto-paracrine growth stimulator that is an important positive modulator of cancer development. We provide preliminary evidence that a loss of imprinting (LOI), or biallelic expression, is an age-related specific epigenetic alteration that occurs in the peripheral prostate of the human. The imprinting of IGF-II in adult tissues is typically maintained and LOI is a common attribute of prostate cancers. Since DNA methylation is a major determinant of IGF-II imprinting we would anticipate that changes in methylation would be associated with altered imprinting status. It is our hypothesis to be tested that a loss of genomic imprinting in IGF-II is an age-related event in prostate epithelial cells and may be modulated by changes in DNA methylation.
In Specific Aim 1, we will determine if a LOI of IGF-II occurs in the aging mouse prostate.
In Specific Aim 2, the impact of accelerating DNA methylation loss on imprinting in mouse and an in vitro human model will be assessed.
Specific Aim 3 will determine whether these mechanisms, and/or others, engender the increase in IGF-II expression seen in aging. This proposal is significant and novel in that it has the ability to provide a critical epigenetic link between the aging process, diet and prostate carcinogenesis in vivo. We expect to determine whether IGF-II imprinting is altered with aging and whether altered DNA methylation is an underlying mechanism for this. Even in the unlikely event the IGF-II plays only a minor role in prostate carcinogenesis, this proposal represents a novel and important methodological approach to evaluating epigenetic field changes that may explain the age-, organ- and diet-related specificity of prostate cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097131-04
Application #
6898691
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Ault, Grace S
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$248,250
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Yang, Bing; Damaschke, Nathan; Yao, Tianyu et al. (2015) Pyrosequencing for accurate imprinted allele expression analysis. J Cell Biochem 116:1165-70
Damaschke, Nathan A; Yang, Bing; Blute Jr, Michael L et al. (2014) Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. Neoplasia 16:1018-27
Yang, Bing; Wagner, Jennifer; Damaschke, Nathan et al. (2014) A novel pathway links oxidative stress to loss of insulin growth factor-2 (IGF2) imprinting through NF-?B activation. PLoS One 9:e88052
Yang, Bing; Wagner, Jennifer; Yao, Tianyu et al. (2013) Pyrosequencing for the rapid and efficient quantification of allele-specific expression. Epigenetics 8:1039-42
Slezak, Jon; Truong, Matthew; Huang, Wei et al. (2013) HP1? expression is elevated in prostate cancer and is superior to Gleason score as a predictor of biochemical recurrence after radical prostatectomy. BMC Cancer 13:148
Truong, Matthew; Yang, Bing; Livermore, Andrew et al. (2013) Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. J Urol 189:2335-41
King, Andre C; Livermore, Andrew; Laurila, Timo A J et al. (2013) Impact of immediate TRUS rebiopsy in a patient cohort considering active surveillance for favorable risk prostate cancer. Urol Oncol 31:739-43
Yang, Bing; Bhusari, Sachin; Kueck, Jessica et al. (2013) Methylation profiling defines an extensive field defect in histologically normal prostate tissues associated with prostate cancer. Neoplasia 15:399-408
Truong, Matthew; Yang, Bing; Wagner, Jennifer et al. (2013) Analysis of promoter non-CG methylation in prostate cancer. Epigenomics 5:65-71
Damaschke, N A; Yang, B; Bhusari, S et al. (2013) Epigenetic susceptibility factors for prostate cancer with aging. Prostate 73:1721-30

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