The natural history of prostate cancer represents an intriguing variation of the multistep process of carcinogenesis. It is clearly established that life-threatening prostate cancer results from low- frequency progression of the common, often microscopic, but clinically insignificant latent form of the disease and not the inexorable growth associated with most small malignancies. Interestingly, both genetic and environmental factors appear to be associated with this rate limiting step. We have observed genetic differences in the susceptibility to ras+myc- induced carcinogenesis using the mouse prostate reconstitution (MPR) model. Our genetic studies using sensitive C57BL/6 mice and the resistant Balb/c mice are consistent with polygenic determinants for carcinogenesis which include a dominant growth suppressor. We have identified a distinct pattern of cAMP mediated gene expression that correlates with sensitivity to ras+myx-induced carcinogenesis in four inbred strains of mice. Marked differences in the prostate specific level of induction by forskolin for c-fos and jun-B were observed in resistant Balb/c and A/J mice but not sensitive C57BL/6 and DBA/2 mice. Chronic exposure to pharmacological levels of testosterone dramatically increased the incidence of ras+myc-induced carcinomas in resistant Balb/c mice and appears to suppress levels of jun-B mRNA. In a large panel of cell lines derived from ras+myc-induced C57BL/6 carcinomas, we have demonstrated a second novel mechanism through which tumor suppressor activity may be eliminated. In 6 out of 7 tumor cell lines, stabilization of wild-type p53 protein was observed indicating this biological feature was highly selected for during progression. We will continue to focus on genetically programmed resistance/susceptibility to ras+myc-induced carcinogenesis using the MPR system. Functional criteria for evaluating a role in carcinogenesis for the observed cAMP-mediated hypersensitive pattern of induction for specific AP-1 complex genes will be established and additional regulators of AP-1 activity including phorbol esters in ras+myc- sensitive and resistant mice will be evaluated. The genes responsible for prostate specific AP-1 induction will be mapped together with the tumorigenic response to ras+myc using recombinant inbred mice. We will further test a role for jun-B as a tumor suppressor gen in ras+myc- resistant Balb/c mice by firmly establishing its regulation by testosterone and directly linking its expression with reduced tumorigenicity in gene transfer studies. We will investigate the mechanism of stabilization of wild type p53 protein in established cell lines and determine its biological significance by comparing similarly derived cell lines which demonstrate this activity to those that do not. Finally, we will extend and explore an observed suppression of ras+myc- induced carcinogenesis by specific retinoids and examine possible relationships to our candidate tumor suppressor gene activities.
Showing the most recent 10 out of 65 publications