Disruption of growth hormone signaling retards prostate carcinogenesis in the Probasin/TAg rat.

Abstract

We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer.

• Authors: Zhuohua Wang, Raul M Luque, Rhonda D Kineman, Vera H Ray, Konstantin T Christov, Daniel D Lantvit, Tomoyuki Shirai, Samad Hedayat, Terry G Unterman, Maarten C Bosland, Gail S Prins, Steven M Swanson
• Journal: Endocrinology (Endocrinology) Vol. 149 Issue 3 Pg. 1366-76 (Mar 2008) ISSN: 0013-7227 [Print] United States
• PMID: 18079205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgen-Binding Protein
• Antigens, Viral, Tumor
• RNA, Messenger
• Receptors, Androgen
• Receptors, Somatotropin
• probasin
• Testosterone
• Insulin-Like Growth Factor I
• Growth Hormone
• Receptor, IGF Type 1

Topics

• Adenocarcinoma (metabolism, pathology, prevention & control)
• Androgen-Binding Protein (genetics, metabolism)
• Animals
• Animals, Genetically Modified
• Antigens, Viral, Tumor (genetics, metabolism)
• Disease Models, Animal
• Down-Regulation (genetics)
• Growth Hormone (genetics, metabolism)
• Insulin-Like Growth Factor I (metabolism)
• Male
• Mutation (genetics)
• Prostate (metabolism, pathology)
• Prostatic Neoplasms (metabolism, pathology, prevention & control)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 1 (metabolism)
• Receptors, Androgen (metabolism)
• Receptors, Somatotropin
• Signal Transduction (genetics, physiology)
• Testosterone (blood)