Biological Sciences Division
Published February 2, 2016 | Version v1
Journal article Open

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

Creators

  • 1. University of Chicago
  • 2. University of Illinois at Urbana-Champaign
  • 3. The Scripps Research Institute
  • 4. Memorial Sloan Kettering Cancer Center
  • 5. Texas A&M University

Description

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.

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Additional details

Identifiers

DOI
10.7554/eLife.12792
Other
oai:uchicago.tind.io:9963

Funding

Susan G. Komen for the Cure
Postdoctoral Fellowship
U.S. Department of Defense
Breast Cancer Research Program Breakthrough Award
National Institutes of Health
R01
National Institutes of Health
Postdoctoral Training Grant
National Institutes of Health
P41
National Science Foundation
CFF
National Science Foundation
XSEDE
Virginia and D.K. Ludwig Fund for Cancer Research

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research