ALTERED IMMUNE/INFLAMMATORY PATHWAY IN RACIALLY DIVERSE PROSTATE CANCERS

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Prostate cancer (Pea) is a major cause for morbidity and mortality in aging men. Androgen receptor (AR) expression and response to androgens (pathways) in prostate epithelial (PE) cells are key determinants of PCa. Interestingly, there exists a strong androgen regulated immune/ inflammatory signature within the PE cells. In the normal PE, androgens promote anti-tumor acute inflammation and suppress pro-tumor chronic inflammation pathway. Since inflammation of the prostate is the earliest known precursor of prostate cancer therefore altered expression or genetic differences in the genes involved in mediating androgen dependent inflammatory/ immune response can be a risk factor for the development of prostate cancer. Can these genetic differences within the androgen regulated immune/ inflammatory pathways also account for the higher incidence of PCa in African American men? In order to address this question we propose that ""The observed racial disparity in prostate cancer incidence is due to genetic differences in the expression/ polymorphism within a group of androgen regulated immune/ inflammatory pathway and that the genes within this pathway can be used as effective prognostic markers of prostate cancer in racially diverse populations". The results will demonstrate that the perturbations in the androgen dependent inflammatory/ immune response pathway can lead to a locally (prostate) compromised immune response that pre-disposes to PCa or following acquisition of androgen independence, promotes the development of aggressive PCa in African Americans. The project will analyze expression of the following gene set: Acute: IFNG, IFNA, MX1, OAS1, PKR, CXCL10 and Chronic : IL6, JUNB, CEBPD, GP130. In addition analysis of specific SNPs in IFNG, IL6, OAS1, MX1 and PKR is also proposed. The samples will consist of normal prostate and prostate cancer tissue obtained from African-American and Caucasian men. The highest incidence rates for Pea and mortality in the world are among African-American men. The alterations in the immune/ inflammatory pathway due to de-regulated expression or genetic polymorphism can provide the molecular basis of higher prostate cancer incidence in African-American men. The proposed studies will address these molecular mechanisms. An understanding of these risk factors for cancer thus has practical importance for prognosis, public health efforts, genetic and nutritional education and developing better treatment regimens.