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

Oncogene volume 24, pages 4736–4740 (2005)Cite this article

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.

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Abbreviations

IGF-I:

insulin-like growth factor I

GH:

growth hormone

GHRH-R:

growth hormone releasing hormone receptor

IGFBP-3:

insulin-like growth factor binding protein-3

TRAMP:

transgenic adenocarcinoma of the mouse prostate

PIN:

prostatic intraepithelial neoplasia

nt:

nucleotide

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Acknowledgements

We thank Dr Michael Ittmann for assistance with pathological examination of the mouse tissues, Julie Bédard for the work on GHRH-R mRNA detection, Kathy-Ann Forner, Scott Hartigan and Danielle Couture for technical assistance with the breeding program, and Martine Bourdeau for assistance in Ki-67 immunostains. This work was funded by CPCRI-IDEA to Dr M Pollak. P Gaudreau is recipient of a scholarship chercheur-boursier national from FRSQ.

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Author notes

  1. Paula J Kaplan-Lefko

    Present address: Amgen Inc., Thousand Oaks, CA, USA

Authors and Affiliations

  1. 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

    Noreen Majeed, Marie-José Blouin, Jane Barry-Shaw & Michael Pollak

  2. Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX, USA

    Paula J Kaplan-Lefko

  3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Norman M Greenberg

  4. Laboratory of Neuroendocrinology of Aging, Department of Medicine, University of Montreal, Montreal, Quebec, Canada

    Pierrette Gaudreau

  5. Department of Pathology, McGill University and Jewish General Hospital, Montreal, Quebec, Canada

    Tarek A Bismar

Authors
  1. Noreen Majeed
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Correspondence to Michael Pollak.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Majeed, N., Blouin, MJ., Kaplan-Lefko, P. et al. A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24, 4736–4740 (2005). https://doi.org/10.1038/sj.onc.1208572

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