Receptor isoform and ligand-specific modulation of dihydrotestosterone- induced prostate specific antigen gene expression and prostate tumor cell growth by estrogens

Yuan Shan Zhu, Li Qun Cai, Ying Huang, Jason Fish, Lu Wang, Zhi Kai Zhang, Julianne L. Imperato-McGinley

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Androgens via the androgen receptor (AR) play crucial roles in prostate physiology and pathophysiology. These androgen actions can be either inhibited or potentiated by estrogens. The mechanisms of these seemingly opposing estrogen effects are unclear. We studied the effects of estrogens on the modulation of androgen induction of prostate specific antigen (PSA) gene expression and prostate tumor cell growth. Cotransfection analyses in CV-1, DU-145, and PC-3 cells showed that dihydrotestosterone (DHT)-induced PSA transcription activity was inhibited by 17β-estradiol, diethylstilbestrol, ICI182780, and 17α-estradiol, but not by tamoxifen via estrogen receptor α (ERα). In the presence of ERβ, 17β-estradiol and diethylstilbestrol had no significant effect, while 17α-estradiol inhibited and ICI182780 and tamoxifen potentiated DHT action. When both ERα and ERβ were present, all ER-ligands except tamoxifen inhibited DHT action. The inhibition of DHT action by 17β-estradiol via ERα was mainly dependent on the DNA binding domain, while the 17α-estradiol effect was mainly dependent on the ERα carboxyl terminus. Treatment with DHT in LAPC-4 prostate tumor cells that express a wild-type AR and both ERβ and ERα greatly increased the PSA gene expression and cell growth. These DHT effects were significantly attenuated by the addition of 17α-estradiol, 17β-estradiol, or cyproterone acetate in a dose-dependent manner. These results indicate that estrogens produce an ER-isoform- and ER-ligand-specific modulation of DHT induction of PSA gene expression and prostate tumor cell growth, providing a molecular basis for designing favorable agents for the prevention and control of prostate cancer.

Original languageEnglish (US)
Pages (from-to)500-508
Number of pages9
JournalJournal of Andrology
Volume26
Issue number4
DOIs
StatePublished - Jul 1 2005

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Keywords

  • Androgen receptor
  • Androgens
  • Estrogen receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Reproductive Medicine
  • Endocrinology
  • Urology

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