The human prostate is androgen dependent and prostate cancer (CaP) maintains this dependence on androgens. It undergoes apoptosis and regression following androgen withdrawal but eventually recurs in the absence of testicular androgens. We are studying a human CaP xenograft (CWR22) that retains these biological characteristics including regression following androgen withdrawal and recurrence after several months in the absence of androgen. Following the withdrawal of androgen stimulation, androgen receptor (AR) levels decrease in CWR22. However, the recurrent tumor CWR22R expresses a high level of AR relative to the androgen- withdrawn CWR22. In the recurrent tumor AR exhibits intense nuclear immunostaining suggests it is activated in the absence of androgen. Moreover, androgen-regulated mRNAs that decreased following androgen withdrawal are up-regulated in CWR22R in the absence of androgen stimulation. The goal of the research will be to establish the role of AR in mediating recurrent gene expression and cellular growth using the CWR22/CWR22R model.
Specific Aims of this part of the proposal are to: 1. Identify mechanisms controlling the different steady state expression levels of AR mRNA and protein in androgen withdrawn CWR22 and CWR22R. 2. Determine the activation state of AR in the recurrent tumor, CW22R, and the role of growth factor signalling in AR activation. 3. Identify androgen-regulated genes in CW22 and determine their expression levels in CWR22R. A closely related Aim 4 will further characterize the mutant AR (H874Y) which is expressed in CWR22 and has an altered steroid binding specificity. Activation of the mutant AR by dihydrotestosterone is normal in transcription assays but response to the adrenal-derived dehydroepiandrosterone (DHEA) is greater than wild-type AR. We will determine relative responsiveness of CWR22 and CWR22R to testicular androgens and the ability of this mutant AR to mediate gene activation and growth effects of DHEA. It is expected that this research will delineate the role of AR and contribute to a better understanding of gene regulation and growth in recurrent CaP.
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