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This version published online on September 1, 2005
Endocrinology, doi:10.1210/en.2005-0607
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Submitted on May 18, 2005
Accepted on August 22, 2005

Disruption of Growth Hormone Signaling Retards Early Stages of Prostate Carcinogenesis in the C3(1)/Tag Mouse

ZHUOHUA WANG, GAIL S. PRINS, KAREN T. COSCHIGANO, JOHN J. KOPCHICK, JEFFREY E. GREEN, VERA H. RAY, SAMAD HEDAYAT, KONSTANTIN T. CHRISTOV, TERRY G. UNTERMAN, and STEVEN M. SWANSON*

Departments of Medicinal Chemistry and Pharmacognosy (Z.W., S.M.S.), Surgical Oncology (S.M.S., KTC) Math, Statistics, and Computer Science (S.H.) and Medicine (T.G.U.), University of Illinois at Chicago, Chicago, IL, 60612; Department of Veterans Affairs Jesse Brown Medical Center (T.G.U.), Chicago, IL, 60612; Edison Biotechnology Institute and Department of Biomedical Sciences, Ohio University, Athens, OH (K.T.C., J.J.K.); Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD (J.E.G.); Provident Hospital of Cook County, Chicago, IL (V.H.R.)

* To whom correspondence should be addressed. E-mail: swanson{at}uic.edu.

Recent epidemiological studies suggest that elevated serum titers of insulin-like growth factor I (IGF-I), which are, to a large degree, regulated by growth hormone (GH), are associated with an increase in prostate cancer risk. The purpose of the current study was to develop the first animal models to directly test the hypothesis that a normal, functional GH/IGF-I axis is required for prostate cancer progression. The GH receptor (GHR) gene-disrupted mouse (Ghr-/-), which has less than 10% of the plasma IGF-I found in GHR wild-type mice, was crossed with the C3(1)/Tag mouse, which develops prostatic intraepithelial neoplasia (PIN) driven by the large T antigen (Tag) that progress to invasive prostate carcinoma in a manner similar to the process observed in humans. Progeny of this cross were genotyped and Tag/Ghr+/+ and Tag/Ghr-/- mice were killed at 9 months of age. Seven of 8 Tag/Ghr+/+ mice harbored PIN lesions of various grades. In contrast, only one of the 8 Tag/Ghr-/- mice exhibited atypia (P < 0.01, Fischer's exact test). Disruption of the GHR gene altered neither prostate androgen receptor expression nor serum testosterone titers. Expression of the Tag oncogene was similar in the prostates of the two mouse strains. Immunohistochemistry revealed a significant decrease in prostate epithelial cell proliferation and an increase in basal apoptotic indices. These results indicate that disruption of GH signaling significantly inhibits prostate carcinogenesis.
Key words: Mouse model of prostate cancer • growth hormone/IGF-I axis • Tag




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