1. Cancer Biology
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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

  1. Sean W Fanning
  2. Rinath Jeselsohn
  3. Venkatasubramanian Dharmarajan
  4. Christopher G Mayne
  5. Mostafa Karimi
  6. Gilles Buchwalter
  7. René Houtman
  8. Weiyi Toy
  9. Colin E Fowler
  10. Ross Han
  11. Muriel Lainé
  12. Kathryn E Carlson
  13. Teresa A Martin
  14. Jason Nowak
  15. Jerome C Nwachukwu
  16. David J Hosfield
  17. Sarat Chandarlapaty
  18. Emad Tajkhorshid
  19. Kendall W Nettles
  20. Patrick R Griffin
  21. Yang Shen
  22. John A Katzenellenbogen
  23. Myles Brown
  24. Geoffrey L Greene  Is a corresponding author
  1. University of Chicago, United States
  2. Dana-Farber Cancer Institute, United States
  3. The Scripps Research Institute, United States
  4. University of Illinois at Urbana-Champaign, United States
  5. Texas A&M University, United States
  6. PamGene International, Netherlands
  7. Memorial Sloan Kettering Cancer Center, United States
Research Article
  • Cited 36
  • Views 3,130
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Cite this article as: eLife 2018;7:e37161 doi: 10.7554/eLife.37161

Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

Data availability

X-ray crystallographic data were deposited in the PDB under the accession code 4XI3.

The following data sets were generated

Article and author information

Author details

  1. Sean W Fanning

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9428-0060
  2. Rinath Jeselsohn

    Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Venkatasubramanian Dharmarajan

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  4. Christopher G Mayne

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8905-6569
  5. Mostafa Karimi

    Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  6. Gilles Buchwalter

    Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Gilles Buchwalter, Employee and shareholder of Celgene.
  7. René Houtman

    Nuclear Receptor Group, PamGene International, Den Bosch, Netherlands
    Competing interests
    René Houtman, Employee of PamGene International.
  8. Weiyi Toy

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Colin E Fowler

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  10. Ross Han

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  11. Muriel Lainé

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  12. Kathryn E Carlson

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
  13. Teresa A Martin

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
  14. Jason Nowak

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  15. Jerome C Nwachukwu

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4313-9187
  16. David J Hosfield

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  17. Sarat Chandarlapaty

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4532-8053
  18. Emad Tajkhorshid

    Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8434-1010
  19. Kendall W Nettles

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  20. Patrick R Griffin

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  21. Yang Shen

    Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  22. John A Katzenellenbogen

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    No competing interests declared.
  23. Myles Brown

    Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8213-1658
  24. Geoffrey L Greene

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    For correspondence
    ggreene@uchicago.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6894-8728

Funding

Susan G. Komen (PDF14301382)

  • Sean W Fanning
  • Geoffrey L Greene

National Cancer Institute (CCSG P30 CA08748)

  • Sarat Chandarlapaty

Breast Cancer Research Foundation (BCRF-17-083)

  • John A Katzenellenbogen

National Institutes of Health (R01CA204999)

  • Sarat Chandarlapaty

U.S. Department of Defense (Breakthrough Award W81XWH-14-1-0360)

  • Sean W Fanning
  • Weiyi Toy
  • Colin E Fowler
  • Sarat Chandarlapaty
  • Geoffrey L Greene

National Institutes of Health (R35GM124952)

  • Yang Shen

National Science Foundation (CCF-1546278)

  • Yang Shen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Charles L Sawyers, Memorial Sloan-Kettering Cancer Center, United States

Publication history

  1. Received: March 31, 2018
  2. Accepted: November 28, 2018
  3. Accepted Manuscript published: November 29, 2018 (version 1)
  4. Version of Record published: January 16, 2019 (version 2)

Copyright

© 2018, 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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