Genomic and Functional Analysis of UGT2B17 in Prostate Cells

前列腺癌是美国男性癌症死亡的第二大原因。

Prostate cancer is the second leading cause of death by cancer among males in the United States. Both genetic and environmental factors are likely to contribute to both the risk for development of the disease as well as the progression of the tumors once established. During the past funding cycle our group has made the novel observation that some individuals carry a deletion polymorphism of the gene, UGT2B17 that encodes an enzyme shown to be capable of inactivation of androgens. Our overall hypothesis underlying this project is that an individual carrying fewer than two copies of UGT2B17 would have higher tissue androgen levels because of decreased catabolism. Since androgens are well known as growth factors for prostate cells, we hypothesize that this deletion polymorphism would confer risk for development of prostate cancer. To begin to address this question we will carry out two different lines of investigation. First, in aim one and two, we propose to characterize the polymorphism present in the human population, defining the deletion event from which it arose and it current frequency in different human populations. Importantly, we determine whether this deletion is in linkage disequilibrium with polymorphisms in linked genes capable of metabolizing androgens. This will provide the groundwork for population studies determining association between the mutant UGT2B17 gene and incidence, severity and survival from prostate cancer. Secondly, we will establish the contribution of UGT2B17to the metabolism of androgens using a number of tissue culture cells lines manipulated to express different levels of this enzyme. This will provide functional bases for the genetic studies proposed.