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Updated: May 6, 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

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ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Weiyi Toy1, Yang Shen, Helen Won

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.

Nature Genetics
|November 5, 2013
PubMed

Insights

Mutations in the estrogen receptor (ER) ligand-binding domain (LBD) can cause resistance to hormonal therapies in metastatic breast cancer. These ESR1 mutations promote ER activity, reducing treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Estrogen receptor (ER)-positive breast cancers constitute 70% of cases and are typically sensitive to ER inhibition.
  • Tumor resistance to endocrine therapy in the metastatic setting is a significant clinical challenge.
  • The underlying mechanisms of resistance to estrogen inhibition remain incompletely understood.

Purpose of the Study:

  • To investigate the genetic basis of resistance to endocrine therapy in metastatic ER-positive breast cancer.
  • To identify specific mutations in the estrogen receptor gene (ESR1) associated with treatment refractory disease.

Main Methods:

  • Comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors.
  • Identification and characterization of ESR1 mutations, particularly within the ligand-binding domain (LBD).
  • Molecular dynamics simulations to elucidate the structural and functional impact of identified mutations.

Main Results:

  • Mutations in ESR1 affecting the LBD were identified in 14 out of 80 metastatic ER-positive breast tumors.
  • Recurrent mutations include p.Tyr537Ser, p.Tyr537Asn, and p.Asp538Gly.
  • Molecular simulations suggest these mutations stabilize an active receptor conformation, driving ER-dependent transcription and proliferation independently of estrogen.
  • Mutant ER receptors demonstrated reduced sensitivity to ER antagonists.

Conclusions:

  • Ligand-binding domain mutations in ER (ESR1) are implicated in mediating clinical resistance to hormonal therapy in metastatic breast cancer.
  • These LBD-mutant ER forms contribute to treatment failure by promoting constitutive receptor activity.
  • Development of more potent ER antagonists may offer therapeutic benefits for patients with these specific mutations.

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