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

Citation
Hj. List et al., Effects of antiandrogens on chromatin remodeling and transcription of the integrated mouse mammary tumor virus promoter, EXP CELL RE, 260(1), 2000, pp. 160-165
Citations number
29
Categorie Soggetti
Cell & Developmental Biology
Journal title
EXPERIMENTAL CELL RESEARCH
ISSN journal
00144827 → ACNP
Volume
260
Issue
1
Year of publication
2000
Pages
160 - 165
Database
ISI
SICI code
0014-4827(20001010)260:1<160:EOAOCR>2.0.ZU;2-T
Abstract
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.