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Updated: Feb 11, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

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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Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation

L Gelsomino1, S Panza1, C Giordano2

  • 1Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, Rende, Italy.

Cancer Letters
|April 28, 2018
PubMed

Insights

Estrogen receptor alpha (ERα) mutations in breast cancer drive stem cell traits and metastasis through ER/NOTCH4 signaling. Early detection and NOTCH inhibitors may offer new precision medicine strategies for mutant-positive patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Recurrent mutations in the estrogen receptor alpha (ERα/ESR1) hormone binding domain (HBD) are detected in endocrine therapy-resistant and metastatic breast cancers.
  • Understanding the functional impact of these HBD-ESR1 mutations is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To investigate the role of HBD-ESR1 mutations in influencing the behavior of breast cancer stem cells (BCSCs).
  • To explore the interplay between ERα mutations, stemness pathways, and NOTCH signaling in breast cancer progression.

Main Methods:

  • Utilized breast cancer cell lines stably expressing wild-type (WT) or mutant (Y537N, Y537S, D538G) ERα.
  • Assessed stem cell characteristics including CD44+/CD24- ratio, stemness gene expression, Mammosphere Forming Efficiency (MFE), self-renewal, and migration.
  • Investigated the impact of NOTCH signaling blockade and ERα phosphorylation at serine 118.

Main Results:

  • Mutant ERα clones exhibited increased stemness markers, MFE, self-renewal, and migration compared to WT-ERα clones.
  • Mutant cells showed elevated NOTCH pathway activation, and NOTCH inhibition reduced MFE and migration.
  • ERα phosphorylation at serine 118 was essential for MFE and NOTCH4 activation in mutant cells.

Conclusions:

  • HBD-ESR1 mutations promote breast cancer stem cell traits via an ERα/NOTCH4 signaling axis.
  • Early detection of HBD-ESR1 mutations is vital for precision medicine.
  • Targeting NOTCH signaling may represent a therapeutic approach to prevent disease progression and metastasis in patients with ERα-mutated breast cancer.
Keywords:
Breast cancerESR1 mutationsNOTCH signaling pathwayStemnessTailored therapy

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