Disruption of growth hormone signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse.
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.
Wang
Zhuohua
Z
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60612-7231, USA.
Prins
Gail S
GS
Coschigano
Karen T
KT
Kopchick
John J
JJ
Green
Jeffrey E
JE
Ray
Vera H
VH
Hedayat
Samad
S
Christov
Konstantin T
KT
Unterman
Terry G
TG
Swanson
Steven M
SM
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D013006:Growth Hormone / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011467:Prostate / Q000473:pathology / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000517:prevention & control*; D011944:Receptors, Androgen / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000172:deficiency*; D015398:Signal Transduction; D013739:Testosterone / Q000097:blood
D000943:Antigens, Differentiation; D000952:Antigens, Polyomavirus Transforming; D011944:Receptors, Androgen; D011986:Receptors, Somatotropin; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone