Differential Mechanisms of Androgen Resistance
Annual summary rept. 22 Nov 2004-21 Nov 2007
MICHIGAN UNIV ANN ARBOR
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We proposed to study the mechanisms of androgen resistance by focusing on androgen receptor mutations that may arise due to selective pressures of antiandrogen treatment. We have utilized xenograft models and a humanized mouse model hmAR xTRAMP of prostate cancer. Novel AR mutations were found throughout the entire coding region of AR although they did not segregate into distinct regions based on hormonal treatment as was previously reported. Functional analysis of some of these mutations was carried out. Preliminary analysis suggests some AR variants show differential action on different promoters and in different cell types suggesting promoter and cell specific effects. Interestingly a high number of mutations occurred in treated mice when compared to non treated mice supporting a role for treatment in AR variant generation. Analysis of tumor progression in the hmAR X TRAMP mice have highlighted differences in disease course between antiandrogen treated and hormone deplete castrated mice. Utilization of mhARxTRAMP mice provided us with a tool to better understand the mechanisms of androgen resistance in prostate cancer and will aid research into more effective treatments.
- Medicine and Medical Research