A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model.
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.
Majeed
Noreen
N
Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Oncology, McGill University, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
Blouin
Marie-José
MJ
Kaplan-Lefko
Paula J
PJ
Barry-Shaw
Jane
J
Greenberg
Norman M
NM
Gaudreau
Pierrette
P
Bismar
Tarek A
TA
Pollak
Michael
M
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D015398:Signal Transduction; D013534:Survival
D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor