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

• Published in: Endocrinology (Philadelphia) Vol. 146; no. 12; pp. 5188 - 5196
• Main Authors: Wang, Zhuohua, Prins, Gail S., Coschigano, Karen T., Kopchick, John J., Green, Jeffrey E., Ray, Vera H., Hedayat, Samad, Christov, Konstantin T., Unterman, Terry G., Swanson, Steven M.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.12.2005; Oxford University Press
• Subjects: Androgen receptors; Animal models; Animals; Antigens; Antigens, Differentiation - metabolism; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Apoptosis; Biological and medical sciences; Carcinogenesis; Carcinogens; Cell Differentiation; Cell Proliferation; Disruption; Epidemiology; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Fundamental and applied biological sciences. Psychology; Genetic crosses; Growth Hormone - metabolism; Growth hormones; Health risks; Immunohistochemistry; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Male; Mice; Mice, Knockout; Mice, Transgenic; Prostate - pathology; Prostate - physiopathology; Prostate cancer; Prostate carcinoma; Prostatic intraepithelial neoplasia; Prostatic Neoplasms - etiology; Prostatic Neoplasms - prevention & control; Receptors; Receptors, Androgen - metabolism; Receptors, Somatotropin - deficiency; Signal Transduction; Testosterone; Testosterone - blood; Vertebrates: endocrinology; Rodentia; Somatotropin hormone; Early stage; Antigen; Signal transduction; Vertebrata; Mammalia; Adenohypophyseal hormone; Mouse; Animal; Disruption; Urogenital system; Prostate
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-0607

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.