Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells

Abstract

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

Data availability

All protein crystal structures have been deposited in the PDB under accession codes: 6PSJ, 7KBS, 7UJC, 7UJ8, 7UJM, 7UJY, 7UJF, 7UJW, 7UJO, 7UJ7, 6V8T, and 6VPF.

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Article and author information

Author details

  1. David J Hosfield

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  2. Sandra Weber

    Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  3. Nan-Sheng Li

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Madline Suavage

    Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  5. Carstyn F Joiner

    Department of Cancer Biology, Loyola University Chicago, Maywood, United States
    Competing interests
    No competing interests declared.
  6. Govinda R Hancock

    Department of Cancer Biology, Loyola University Chicago, Maywood, United States
    Competing interests
    No competing interests declared.
  7. Emily A Sullivan

    Department of Cancer Biology, Loyola University Chicago, Maywood, United States
    Competing interests
    No competing interests declared.
  8. Estelle Ndukwe

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

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

    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. Sylvie C Mader

    Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  13. Geoffrey L Greene

    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:" 0000-0001-6894-8728
  14. Sean W Fanning

    Department of Cancer Biology, Loyola University Chicago, Maywood, United States
    For correspondence
    sfanning@luc.edu
    Competing interests
    Sean W Fanning, In the interest of transparency, Dr. Fanning's laboratory receives sponsored research funds from Olema Oncology Inc. Olema was not involved in this study. This work has no impact on the company..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9428-0060

Funding

Susan G. Komen (CCR19608597)

  • Sean W Fanning

Ludwig Fund for Metastasis Research

  • Geoffrey L Greene

Canadian Institutes of Health Research

  • Sylvie C Mader

The funders had no role in the execution of this study.

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Version history

  1. Received: July 27, 2021
  2. Preprint posted: August 28, 2021 (view preprint)
  3. Accepted: May 13, 2022
  4. Accepted Manuscript published: May 16, 2022 (version 1)
  5. Accepted Manuscript updated: May 17, 2022 (version 2)
  6. Version of Record published: June 8, 2022 (version 3)
  7. Version of Record updated: July 27, 2022 (version 4)

Copyright

© 2022, Hosfield 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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  1. David J Hosfield
  2. Sandra Weber
  3. Nan-Sheng Li
  4. Madline Suavage
  5. Carstyn F Joiner
  6. Govinda R Hancock
  7. Emily A Sullivan
  8. Estelle Ndukwe
  9. Ross Han
  10. Sydney Cush
  11. Muriel Lainé
  12. Sylvie C Mader
  13. Geoffrey L Greene
  14. Sean W Fanning
(2022)
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells
eLife 11:e72512.
https://doi.org/10.7554/eLife.72512

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https://doi.org/10.7554/eLife.72512

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