Effects of antiandrogens on chromatin remodeling and transcription of the integrated mouse mammary tumor virus promoter

Inhibition of the ligand-activated androgen receptor (AR) by antiandrogens plays an important role in the treatment of various hyperandrogenic disorde rs including prostate cancer. However, the molecular mechanisms of antiandr ogen activity in vivo remain unclear. In this study we analyzed the effects of cyproterone acetate (CPA), flutamide (F), and hydroxyflutamide (OHF) on transcriptional activation and chromatin remodeling of the genomically int egrated mouse mammary tumor virus (MMTV), promoter. This promoter has provi ded an excellent model system to study the impact of steroid hormones on tr anscriptional activation in the context of a defined chromatin structure. T he MMTV hormone response element is positioned on a phased nucleosome, whic h becomes remodeled in response to steroids. We utilized this model system in mouse L-cell fibroblasts that contain a stably integrated MMTV promoter. In these cells, dihydrotestosterone (DHT) induced a large increase of AR p rotein levels that correlated with transcriptional activation and chromatin remodeling of the MMTV promoter Coadministration of DHT and CPA or DHT and OHF in these cells inhibited the increase of AR levels, which resulted in a strong blockage of transcriptional activation and chromatin remodeling of the MMTV promoter. In contrast, F had no significant influence on these ac tivities, We conclude that a major portion of the antiandrogenic effects of CPA and OHF in vivo are mediated by the reduction of AR levels. (C) 2000 A cademic Press.