A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model.

Abstract

Circulating insulin-like growth factor-I (IGF-I) levels have been shown to be related to risk of prostate cancer in epidemiologic studies. While specific genetic loci responsible for interindividual variation in circulating IGF-I levels in normal men have not been identified, candidate genes include those involved in the growth hormone (GH)-IGF-I axis such as the hypothalamic factors GH releasing hormone (GHRH) and somatostatin and their receptors. To investigate the role of the GH-IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I. The lit mutation significantly reduced the percentage of the prostate gland showing neoplastic changes at 35 weeks of age (P=0.0005) and was also associated with improved survival (P<0.01). These data provide an example of a germ line mutation that reduces risk in an experimental prostate carcinogenesis model. The results suggest that prostate carcinogenesis and progression may be influenced by germ line variation of genes encoding signalling molecules in the GH-IGF-I axis.

• Authors: Noreen Majeed, Marie-José Blouin, Paula J Kaplan-Lefko, Jane Barry-Shaw, Norman M Greenberg, Pierrette Gaudreau, Tarek A Bismar, Michael Pollak
• Journal: Oncogene (Oncogene) Vol. 24 Issue 29 Pg. 4736-40 (Jul 07 2005) ISSN: 0950-9232 [Print] England
• PMID: 15870705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• Insulin-Like Growth Factor I
• Growth Hormone
• somatotropin releasing hormone receptor

Topics

• Animals
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Disease Progression
• Genetic Predisposition to Disease
• Germ-Line Mutation
• Growth Hormone (blood)
• Humans
• Insulin-Like Growth Factor I (analysis)
• Male
• Mice
• Prostatic Neoplasms (genetics, pathology)
• Receptors, Neuropeptide (genetics)
• Receptors, Pituitary Hormone-Regulating Hormone (genetics)
• Signal Transduction
• Survival