Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice

Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice

^*Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park, Research Division, P.O. Box 389, Smithville, TX 78957; and ^§Department of Cell and Molecular Biology, Ciemat Instituto, 28040 Madrid, Spain

Communicated by Michael Potter, National Institutes of Health, Bethesda, MD (received for review October 31, 1999)

Abstract

Transgenic mice expressing human insulin-like growth factor 1 (IGF-1) in basal epithelial cells of prostate have been characterized. Transgene expression led to activation of the IGF-1 receptor and spontaneous tumorigenesis in prostate epithelium. Hyperplasia was evident in these mice by 2–3 months of age. Atypical hyperplasias and prostatic intraepithelial neoplasia were evident by 6–7 months of age. Well differentiated adenocarcinomas appeared in mice 6 months or older. Less differentiated tumors, diagnosed as small cell carcinomas, were also observed in two of the older mice. Both lobes of the mouse prostate gland (dorsolateral and ventral) presented preneoplastic and neoplastic changes. The incidence of tumors in mice ≥6 months of age (38 mice total) was 50%. The development of neoplasia in these transgenic mice appeared to follow a stepwise progression through early preneoplastic changes that ultimately culminated in frank neoplasia. These mice offer an animal model for prostate cancer that will allow study of the stepwise development of this disease and the mechanism(s) whereby IGF-1 mediates this process.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: sa83107{at}odin.mdacc.tmc.edu.
↵ ‡ Present address: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000.
Abbreviations:

IGF-1,

insulin-like growth factor 1;

IGF-1r,

insulin-like growth factor-1 receptor;

MUP,

major urinary protein;

BK5,

bovine keratin 5;

IGFBP-3,

IGF binding protein 3;

PIN,

prostatic intraepithelial neoplasia;

PI3,

phosphatidylinositol 3