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 disorders including prostate cancer. However, the molecular mechanisms of antiandrogen 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 integrated mouse mammary tumor virus (MMTV) promoter. This promoter has provided an excellent model system to study the impact of steroid hormones on transcriptional activation in the context of a defined chromatin structure. The MMTV hormone response element is positioned on a phased nucleosome, which 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 protein 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 activities. We conclude that a major portion of the antiandrogenic effects of CPA and OHF in vivo are mediated by the reduction of AR levels.
List
H J
HJ
Departments of Oncology, Georgetown University, Washington, D.C 20007, USA.
Smith
C L
CL
Martinez
E
E
Harris
V K
VK
Danielsen
M
M
Riegel
A T
AT
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000187:drug effects*; D017373:Cyproterone Acetate / Q000494:pharmacology; D015342:DNA Probes / Q000235:genetics; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D007739:L Cells; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000187:drug effects* / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000726:Androgen Antagonists; D002843:Chromatin; D015342:DNA Probes; D011944:Receptors, Androgen; C014290:hydroxyflutamide; D017373:Cyproterone Acetate; D005485:Flutamide