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 ofPCa. Interestingly, there exists a strong androgen regulated immune/ inflammatory signature within the PEcells. In the normal PE, androgens promote anti-tumor acute inflammation and suppress pro-tumor chronicinflammation pathway. Since inflammation of the prostate is the earliest known precursor of prostate cancertherefore altered expression or genetic differences in the genes involved in mediating androgen dependentinflammatory/ immune response can be a risk factor for the development of prostate cancer. Can thesegenetic differences within the androgen regulated immune/ inflammatory pathways also account for thehigher incidence of PCa in African American men? In order to address this question we propose that ''Theobserved 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 geneswithin this pathway can be used as effective prognostic markers of prostate cancer in racially diversepopulations'. 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-disposesto PCa or following acquisition of androgen independence, promotes the development of aggressive PCa inAfrican 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 inIFNG, IL6, OAS1, MX1 and PKR is also proposed. The samples will consist of normal prostate and prostatecancer tissue obtained from African-American and Caucasian men. The highest incidence rates for Pea andmortality in the world are among African-American men. The alterations in the immune/ inflammatorypathway due to de-regulated expression or genetic polymorphism can provide the molecular basis of higherprostate cancer incidence in African-American men. The proposed studies will address these molecularmechanisms. 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.
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