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.

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

  • 4,350
    views
  • 672
    downloads
  • 77
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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

Share this article

https://doi.org/10.7554/eLife.37161

Further reading

    1. Cancer Biology
    2. Cell Biology
    Ida Marie Boisen, Nadia Krarup Knudsen ... Martin Blomberg Jensen
    Research Article

    Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.

    1. Cancer Biology
    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.