Related Experiment Video

Updated: Mar 26, 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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Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing

Sean W Fanning1, Christopher G Mayne2,3,4, Venkatasubramanian Dharmarajan5

  • 1Ben May Department for Cancer Research, University of Chicago, Chicago, United States.

Elife
|February 3, 2016
PubMed

Insights

Somatic ESR1 mutations like Y537S and D538G cause endocrine therapy resistance by making estrogen receptor alpha (ERα) constitutively active. These ERα mutants resist antiestrogens due to altered ligand-binding domain dynamics.

Area of Science:

  • Molecular biology
  • Structural biology
  • Endocrinology

Background:

  • Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), particularly Y537S and D538G, are associated with acquired resistance to endocrine therapies.
  • Previous cell-based studies indicated that these ERα mutants exhibit constitutive activity and resistance to antiestrogens, suggesting ligand-binding domain (LBD) dysfunction.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ESR1 mutations (Y537S, D538G) confer constitutive activity and antiestrogen resistance to ERα.
  • To integrate biophysical and structural data for a comprehensive understanding of mutant ERα function.

Main Methods:

  • Biophysical assays to assess protein-ligand interactions and coactivator recruitment.
  • Structural biology techniques to analyze the conformational changes in the ERα ligand-binding domain.

Main Results:

  • Mutant ERα proteins (Y537S, D538G) demonstrate hormone-independent coactivator recruitment.
  • Reduced binding affinities for both the estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) were observed in mutant ERα.
  • Alterations in the conformational dynamics of the Helix 11-Helix 12 loop within the ERα LBD stabilize an agonist-bound state and resist antagonist inhibition.

Conclusions:

  • ESR1 mutations Y537S and D538G lead to a constitutively active ERα phenotype.
  • The altered conformational dynamics of the ERα LBD loop are critical for conferring resistance to antiestrogen therapies.
Keywords:
acquired drug resistancebiophysicsbreast cancerestrogen receptor alphahormonehumanhuman biologymedicineselective estrogen receptor modulatorssomatic mutationstructural biology

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