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

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.

Metrics

  • 3,415
    Page views
  • 515
    Downloads
  • 40
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2018)
The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
eLife 7:e37161.
https://doi.org/10.7554/eLife.37161
  1. Further reading

Further reading

    1. Cancer Biology
    2. Cell Biology
    Johnny M Tkach et al.
    Research Article

    Centrosomes act as the main microtubule organizing center (MTOC) in metazoans. Centrosome number is tightly regulated by limiting centriole duplication to a single round per cell cycle. This control is achieved by multiple mechanisms, including the regulation of the protein kinase PLK4, the most upstream facilitator of centriole duplication. Altered centrosome numbers in mouse and human cells cause p53-dependent growth arrest through poorly defined mechanisms. Recent work has shown that the E3 ligase TRIM37 is required for cell cycle arrest in acentrosomal cells. To gain additional insights into this process, we undertook a series of genome-wide CRISPR/Cas9 screens to identify factors important for growth arrest triggered by treatment with centrinone B, a selective PLK4 inhibitor. We found that TRIM37 is a key mediator of growth arrest after partial or full PLK4 inhibition. Interestingly, PLK4 cellular mobility decreased in a dose-dependent manner after centrinone B treatment. In contrast to recent work, we found that growth arrest after PLK4 inhibition correlated better with PLK4 activity than with mitotic length or centrosome number. These data provide insights into the global response to changes in centrosome number and PLK4 activity and extend the role for TRIM37 in regulating the abundance, localization, and function of centrosome proteins.

    1. Cancer Biology
    2. Cell Biology
    Haoran Zhu et al.
    Research Article

    Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.