Many diseases have immune and inflammatory components. For some cancers, chronic inflammation contributes to the carcinogenic process. For example, inflammatory bowel disease predisposes individuals to colorectal cancer. While prostate cancer is the second leading cancer-related cause of death in men, its etiology remains poorly understood. The incidence of prostate cancer in men is staggeringly high;upwards of 85% of men will develop prostate cancer, although most cases may go undiagnosed. Similarly, inflammation of the prostate, aka, prostatitis, is highly prevalent among men and often has an unknown etiology. Our working hypothesis for this project is that chronic prostatitis predisposes men to developing prostate cancer. We are using transgenic mouse technology to create new models for studying the role of inflammation in prostate cancer pathogenesis.We have created 2 new strains of transgenic mice that over-express inflammatory mediators in the prostate. The first strain expresses the pro-inflammatory cytokine IL-6 in the prostate. We selected IL-6 as a target because it has been associated with prostatic transformation and most prostate cancer cell lines proliferate in response to IL-6 and secrete IL-6, suggesting an autocrine effect of this pro-inflammatory cytokine. The second target is a signal-transducing molecule associated with IL-6, STAT3, which has been known to be associated with oncogenic transformation in many tissue types. Activated STAT3 has been identified in prostate cancer lesions. We have generated a mouse line that expresses a constitutively activated form of STAT3 in the prostate. We have identified founder lines for future study of both transgenic strains. Our initial findings suggest that both transgenic strains develop prostatic intra-epithelial neoplasia (PIN), a precursor lesion for prostate cancer. However, neither strain has been observed to develop advanced tumors or adenocarcinoma. We believe that these findings demonstrate that these two inflammatory mediators can initiate the early stages of prostate cancer, but that other events are required to induce complete transformation. Our on-going studies will identify other genes that may contribute to prostate cancer susceptibility. We will cross our new transgenic lines to mice that are deficient in tumor suppressor genes which have been linked to prostate cancer (e.g., PTEN and p53) and determine whether this causes progression of PIN to adenocarcinoma. To identify potentially novel targets for therapy, additional studies will characterize changes in gene expression associated with PIN and progression to adenocarcinoma. Our long-term goal is to integrate these new models into our studies of immune suppression and cancer. These models may more accurately reflect tumor development in humans and allow us to identify clinically-relevant approaches to enhance immune-based therapies for cancer.