Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

Elife. 2016 Feb 2;5:e12792. doi: 10.7554/eLife.12792.

Abstract

Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

Keywords: acquired drug resistance; biophysics; breast cancer; estrogen receptor alpha; hormone; human; human biology; medicine; selective estrogen receptor modulators; somatic mutation; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Crystallography, X-Ray
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / genetics*
  • Humans
  • Models, Molecular
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation, Missense*
  • Protein Binding
  • Protein Conformation

Substances

  • Antineoplastic Agents
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Mutant Proteins