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

Heinz Joachim List, Catharine L. Smith, Elisabeth Martinez, Violaine K. Harris, Mark Danielsen, Anna T. Riegel

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)160-165
Number of pages6
JournalExperimental Cell Research
Volume260
Issue number1
DOIs
StatePublished - Oct 10 2000
Externally publishedYes

Keywords

  • Androgen receptor
  • Chromatin
  • Cyproterone acetate
  • Flutamide
  • Hydroxyflutamide
  • MMTV promoter
  • Transcription

ASJC Scopus subject areas

  • Cell Biology

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