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

Departments of Medicinal Chemistry and Pharmacognosy (Z.W., S.M.S.) and Urology (G.S.P.), Surgical Oncology (S.M.S., K.T.Ch.), Math, Statistics, and Computer Science (S.H.), and Medicine (T.G.U.), University of Illinois at Chicago, and Department of Veterans Affairs Jesse Brown Medical Center (T.G.U.), Chicago, Illinois 60612; Edison Biotechnology Institute and Department of Biomedical Sciences (K.T.Co., J.J.K.), Ohio University, Athens, Ohio 45701; Laboratory of Cell Regulation and Carcinogenesis (J.E.G.), National Cancer Institute, Bethesda, Maryland 20892; and Provident Hospital of Cook County (V.H.R.), Chicago, Illinois 60615

Address all correspondence and requests for reprints to: Steven M. Swanson, Department of Medicinal Chemistry and Pharmacognosy (M/C 781), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231. E-mail: swanson{at}uic.edu.

Recent epidemiological studies suggest that elevated serum titers of IGF-I, which are, to a large degree, regulated by 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)/T antigen (Tag) mouse, which develops prostatic intraepithelial neoplasia driven by the large 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 eight Tag/Ghr^+/+ mice harbored prostatic intraepithelial neoplasia lesions of various grades. In contrast, only one of the eight 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.

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