1. Structural Biology and Molecular Biophysics
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Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

  1. Sean W Fanning
  2. Christopher G Mayne
  3. Venkatasubramanian Dharmarajan
  4. Kathryn E Carlson
  5. Teresa A Martin
  6. Scott J Novick
  7. Weiyi Toy
  8. Bradley Green
  9. Srinivas Panchamukhi
  10. Benita S Katzenellenbogen
  11. Emad Tajkhorshid
  12. Patrick R Griffin
  13. Yang Shen
  14. Sarat Chandarlapaty
  15. John A Katzenellenbogen
  16. Geoffrey L Greene  Is a corresponding author
  1. University of Chicago, United States
  2. University of Illinois at Urbana-Champaign, United States
  3. The Scripps Research Institute-Scripps Florida, United States
  4. The Scripps Research Institute, United States
  5. Memorial Sloan Kettering Cancer Center, United States
  6. University of Illinois Urbana-Champaign, United States
  7. Texas A&M University, United States
  8. Memorial Sloan-Kettering Cancer Center, United States
Research Article
  • Cited 121
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Cite this article as: eLife 2016;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.

Article and author information

Author details

  1. Sean W Fanning

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Christopher G Mayne

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Venkatasubramanian Dharmarajan

    Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kathryn E Carlson

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Teresa A Martin

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Scott J Novick

    Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Weiyi Toy

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Bradley Green

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Srinivas Panchamukhi

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Benita S Katzenellenbogen

    Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Emad Tajkhorshid

    Department of Biochemistry, Center for Biophysics and Computational Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Patrick R Griffin

    Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yang Shen

    Department of Electrical and Computer Engineering and TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Sarat Chandarlapaty

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. John A Katzenellenbogen

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Geoffrey L Greene

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    For correspondence
    ggreene@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Peter Tontonoz, Howard Hughes Medical Institute, University of California, Los Angeles, United States

Publication history

  1. Received: November 3, 2015
  2. Accepted: January 31, 2016
  3. Accepted Manuscript published: February 2, 2016 (version 1)
  4. Accepted Manuscript updated: February 3, 2016 (version 2)
  5. Version of Record published: March 24, 2016 (version 3)
  6. Version of Record updated: September 18, 2018 (version 4)

Copyright

© 2016, Fanning et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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