The health and normal survival of steroid target tissues is dependent on exposure to adequate levels of steroid hormones. Thus, normal function of the prostate, a steroid target tissue, is dependent on exposure of that organ to adequate levels of male specific steroids, hormones or androgens. Conversely, exposure to extremely high levels of androgens is believed to contribute to malignant transformation of prostate tissue, already the leading cause of cancer-related deaths in the United States. Androgen levels within steroid hormone target tissues such as the prostate are thought to be regulated at least in part by the catabolism of that steroid by UDP-Glucuronosyltransferase 2B17 (UGTB17). Evidence supporting this hypothesis comes from numerous studies demonstrating that the UGT2B17 enzyme reacts with or glucuronidates androgens such as testosterone, dihydrotestosterone, and androsterone. Thus, the UGT2B17 enzyme is important to the catabolism and elimination of androgens by glucuronidation and consequently impacts the levels of circulating steroid in target tissue such as the prostate. The overall aim of this research is to test the hypothesis that aberrant expression of this gene may alter the risk for prostate cancer and that the gene may ultimately be a genetic susceptibility marker for prostate cancer. Towards that goal, it is proposed that the alterations in the gene expression of the UGT2B17 gene by DNA methylation and single nucleotide polymorphisms (SNPs) subsequently impact the normal function and structural integrity of androgen-dependent tissue. Towards that goal, it is proposed that the alterations in the gene expression of the UGT2B17 gene by DNA methylation and single nucleotide polymorphisms (SNPs) subsequently impact the normal function and structural integrity of androgen-dependent tissue. The experiments in this proposal will determine if DNA methylation is 1) altered in the gene promoter of the UGT2B17 gene expressed in a human prostatic carcinoma cell line, LNCaP, in the presence of growth factors that are normally present in the prostate microenvironment 2) altered in other cells of various tissue origin and 3) impacted by the presence of SNPs.
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