The age-dependence and multifocality of prostate cancer are important features of prostate cancer that will be addressed in the present proposal. IGF2, a paracrine and autocrine regulator of cell proliferation, is tightly regulated and maintains a strict imprinted pattern in most normal adult tissues. Genomic imprinting is an epigenetic modification that leads to the differential expression (i.e. only from one allele) of a gene based on parental origin. In the previous cycle of this grant, we found that in the mouse an aging-related, organ-specific loss of imprinting at IGF2 occurs in the dorsolateral prostate associated with increased IGF2 levels. Furthermore, this epigenetic change develops in that subset of histologically normal prostate tissues from men that have associated prostate cancer. The current proposal focuses on testing the hypothesis that age-related IGF2 LOI can be modulated and furthermore, that it accelerates the development of cancer.
Our Specific Aims i nclude: i) testing the impact of IGF2 LOI on prostate carcinogenesis in a susceptible mouse, ii) determining whether interventions that induce CTCF maintain IGF2 imprinting, and iii) define and validate IGF2 LOI in the `field defect'associated with human prostate cancer development. This proposal is novel in that it proposes a paradigm in which genomic imprinting is not `fixed'but may be modulated by external and internal factors in the aging prostate. We expect to determine whether IGF2 imprinting loss can be prevented and the test mechanisms underlying this. The rationale that underlies the proposed research is that by defining the etiology and impact of IGF2 imprinting changes in the prostate, new therapeutic strategies for altering the development of this process will be elucidated. This study is significant in that it has the potential to provide a critical epigenetic link between the aging process and prostate carcinogenesis in vivo. Even in the unlikely event the IGF2 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.

Public Health Relevance

Why prostate cancer develops with aging is unclear, yet the impact of this disease in the aging population is significant and expected to increase. We have defined a novel epigenetic change, the loss of IGF2 imprinting, that occurs with aging and identifies men who have developed the disease. We seek to further define this change in order to develop new therapies to prevent cancer, as well as develop new methods for diagnosing prostate cancer and predicting risk of developing the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097131-09
Application #
8209301
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Snyderwine, Elizabeth G
Project Start
2002-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$257,755
Indirect Cost
$82,143
Name
University of Wisconsin Madison
Department
Urology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Yang, Bing; Damaschke, Nathan; Yao, Tianyu et al. (2015) Pyrosequencing for accurate imprinted allele expression analysis. J Cell Biochem 116:1165-70
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-κB activation. PLoS One 9:e88052
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
Desotelle, Joshua; Truong, Matthew; Ewald, Jonathan et al. (2013) CpG island hypermethylation frequently silences FILIP1L isoform 2 expression in prostate cancer. J Urol 189:329-35
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) HP1γ 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
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; Livermore, Andrew et al. (2013) Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. J Urol 189:2335-41
Truong, Matthew; Yang, Bing; Jarrard, David F (2013) Toward the detection of prostate cancer in urine: a critical analysis. J Urol 189:422-9

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