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Updated: Mar 30, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

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A new class of small molecule estrogen receptor-alpha antagonists that overcome anti-estrogen resistance

Yongxian Ma1, Anju Preet1, York Tomita1,2

  • 1Department of Oncology, Georgetown University School of Medicine, Washington, DC, USA.

Oncotarget
|November 18, 2015
PubMed

Insights

Researchers identified novel small molecules that inhibit estrogen receptor-alpha (ER) activity and restore Tamoxifen sensitivity in resistant breast cancer cells. These compounds show promise for overcoming anti-estrogen resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Previous studies show BRCA1 inhibits estrogen receptor-alpha (ER) activity.
  • Tamoxifen resistance is a significant clinical challenge in ER-positive breast cancer.

Purpose of the Study:

  • To identify small molecules that can overcome Tamoxifen resistance by targeting the ER/BRCA1 interaction.
  • To investigate the mechanism by which BRCA1 influences ER activity in Tamoxifen-resistant cells.

Main Methods:

  • Computational modeling and pharmacophore screening to identify potential drug candidates.
  • In vitro assays using ER-positive breast cancer cell lines (MCF-7, LCC9, LCC2) to assess compound efficacy.
  • In vivo studies using tumor xenografts to evaluate therapeutic potential.

Main Results:

  • Overexpression of BRCA1 inhibited ER activity and partially restored Tamoxifen sensitivity in LCC9 cells.
  • Computational screening identified small molecules that inhibit ER activity, with four compounds showing potent activity in Tamoxifen-resistant cells.
  • Two compounds (4631-P/1 and 35466-L/1) inhibited ER-dependent proliferation, restored Tamoxifen sensitivity, and disrupted BRCA1-ER association.
  • A modified compound (35446 hydrochloride) inhibited LCC9 tumor xenograft growth in vivo.

Conclusions:

  • A novel class of small molecules targeting the ER/BRCA1 interaction can overcome Tamoxifen resistance.
  • These compounds represent a promising therapeutic strategy for patients with Tamoxifen-resistant breast cancer.
Keywords:
BRCA1Tamoxifenagonistantagonistestrogen receptor (ER-α)

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