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Anti-estrogen activity in the yeast transcription system: estrogen receptor mediated agonist response

H Kohno1, O Gandini, S W Curtis

  • 1Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.

Steroids
|October 1, 1994
PubMed

Insights

Yeast cells expressing mouse estrogen receptors showed tamoxifen and hydroxytamoxifen acting as agonists, not antagonists. ICI 164,384 also displayed partial agonist activity, unlike in mammalian systems, due to yeast lacking estrogen receptor degradation pathways.

Area of Science:

  • * Molecular Endocrinology
  • * Yeast Genetics
  • * Drug Mechanism of Action

Background:

  • * Estrogen receptors (ERs) mediate cellular responses to estradiol.
  • * Anti-estrogens like tamoxifen and ICI 164,384 are crucial in hormone-dependent cancer therapy.
  • * Previous studies suggested ER degradation contributes to anti-estrogen resistance in mammalian tissues.

Purpose of the Study:

  • * To investigate the mechanism of anti-estrogen action using a yeast expression system.
  • * To determine if yeast cells replicate the antagonistic effects of anti-estrogens observed in mammalian systems.
  • * To explore the role of estrogen receptor stability in anti-estrogen response.

Main Methods:

  • * Expression of mouse estrogen receptor in Saccharomyces cerevisiae.
  • * Transfection with a VitA2-ERE-CTC1-lacZ reporter gene construct.
  • * Treatment with estradiol, tamoxifen, hydroxytamoxifen, nafoxidine, and ICI 164,384.
  • * Western blot analysis to assess estrogen receptor levels.
  • * Gel-shift assay to evaluate estrogen-responsive element binding.

Main Results:

  • * Tamoxifen and hydroxytamoxifen exhibited full agonist activity in yeast, contrary to their antagonist role in mammals.
  • * ICI 164,384 and ICI 182,780 showed partial agonist activity, failing to antagonize estradiol.
  • * Yeast cells lacked the proteolytic degradation of estrogen receptor observed in ICI 164,384-treated mammalian cells.
  • * ICI-bound estrogen receptor demonstrated the ability to bind an estrogen-responsive element.

Conclusions:

  • * Yeast cells provide a distinct model for studying estrogen receptor pharmacology, lacking mammalian-specific degradation pathways.
  • * The agonist activity of ICI 164,384 in yeast suggests its bound receptor can activate transcription.
  • * This study highlights the importance of cellular context, specifically protein stability, in determining anti-estrogen efficacy.

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