1. ¹Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Oncology, McGill University, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2
2. ²Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX, USA
3. ³Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
4. ⁴Laboratory of Neuroendocrinology of Aging, Department of Medicine, University of Montreal, Montreal, Quebec, Canada
5. ⁵Department of Pathology, McGill University and Jewish General Hospital, Montreal, Quebec, Canada

Correspondence: M Pollak, E-mail: michael.pollak@mcgill.ca

⁶Current address: Amgen Inc., Thousand Oaks, CA, USA

Received 14 December 2004; Revised 19 January 2005; Accepted 19 January 2005; Published online 2 May 2005.

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.