Novel animal models to study the role of the growth hormone insulin-like growth factor I axis in prostate cancer.

Prostate cancer is the most common of any nonskin cancer in the human body. Some recent clinical and epidemiologic studies suggest that the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis may influence prostate carcinogenesis. The purpose of this dissertation study was to establish the first animal models to directly test the hypothesis that a normal, functional GH/IGF-I axis is required for prostate cancer progression. The Tag/Ghr mouse model was established by crossing the GH receptor (GHR) knockout mouse with the C3(1)/Tag mouse, which harbors the large T antigen (Tag) driven to expression in the prostate by the 5-flanking region of the rat C3(1) gene. All progeny carried one allele of Tag and was homozygous for the wild type GHR or null for GHR. Results from this new model showed that progression of prostate cancer from Tag-initiated epithelial cells to prostate intraepithelial neoplasia (PIN) was significantly inhibited in the absence of GHR (incidence of PIN, 70% and 62.5% decrease in dorsal lateral and ventral prostate, P < 0.01; multiplicity of PIN, 28% and 26% decrease in dorsal lateral and ventral prostate, P < 0.05). Disruption of the GHR gene did not alter the expression of Tag oncogene, prostate androgen receptor, or serum testosterone titers. Cancer inhibition appears to be associated with decreased proliferation and increased apoptosis of the prostate epithelium of Tag/Ghr mice. The findings suggest that PIN may require GH signaling for progression. Tag/Gh rat model, which was established by crossing the spontaneous dwarf rat with the Probasin/Tag rat, demonstrated that prostate cancer progression induced by Tag was significantly inhibited in the absence of GH signaling. The prostate tumor incidence was significantly reduced and tumor latency was delayed in Tag/Gh relative to Tag/Gh controls. Also, the tumor burden was significantly reduced in Tag/Gh. At 25 weeks of age, loss of GH resulted in a 20% and 80% decrease (P < 0.05 and P < 0.0001) in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 weeks of age, the invasive prostate adenocarcinomas were observed in 100% of Tag/Gh rats with metastasis found in pelvic lymph nodes and mammary glands, while the majority of Tag/Gh (60%) did not develop invasive tumors. This inhibition is not due