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Peer-reviewedCC BY 4.0Molecular Oncology

Pharmacological chromatin remodeling enhances response to estrogen therapy in ER + breast cancer

  • Anneka L. Johnson Thomas1,2
  • Barbara Karakyriakou1,3
  • Patricia C. Muskus2
  • Alyssa M. Roberts1
  • Justin Rendleman4
  • Alexa Warren1
  • Hanxu Lu1
  • Kimberly A. Birmingham2
  • Malone K. Friedman2
  • Abigail E. Goen1
  • Huijuan Yang1
  • Owen M. Wilkins5
5 more authors
  • Fred W. Kolling6
  • Eugene Demidenko7
  • Julie M. Jorns8
  • Brock C. Christensen1,3
  • Todd W. Miller1,2,8
8 affiliations
  1. 1Department of Molecular and Systems Biology Dartmouth Geisel School of Medicine Lebanon NH USA
  2. 2Department of Pharmacology and Toxicology Medical College of Wisconsin Milwaukee WI USA
  3. 3Department of Epidemiology, Geisel School of Medicine Dartmouth College Lebanon NH USA
  4. 4Laboratory of Genome Architecture and Dynamics The Rockefeller University New York NY USA
  5. 5Department of Biomedical Data Science Geisel School of Medicine at Dartmouth Lebanon NH USA
  6. 6Dartmouth Cancer Center Dartmouth Geisel School of Medicine Hanover NH USA
  7. 7Department of Biostatistics Dartmouth Geisel School of Medicine Lebanon NH USA
  8. 8Department of Pathology Medical College of Wisconsin Milwaukee WI USA
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Abstract

Estrogen therapy elicits clinical benefit in ~ 30% of patients with endocrine‐resistant estrogen receptor (ER)‐positive breast cancer, but its mechanism of action and strategies to increase efficacy remain unclear. Estrogen therapy can induce ER transcriptional hyperactivation and DNA damage; we postulated that such damage could be exacerbated by epigenetic dysregulation via inhibition of histone deacetylases (HDACi). We evaluated the effects of 17b‐estradiol and HDACi in three types of ER+ breast cancer models: Cells adapted to growth following long‐term estrogen deprivation; cells engineered to overexpress exogenous ER that confers endocrine resistance; mice bearing endocrine‐resistant patient‐derived xenografts. Assay endpoints included apoptosis, growth, DNA damage, histone post‐translational modification, levels of ER‐regulated transcripts and encoded proteins, cell cycle and replication status, and genome‐wide chromatin accessibility, ER binding, and transcriptional profiles. Entinostat treatment increased histone acetylation and chromatin accessibility. Combination treatment with E2 and entinostat inhibited cell growth and induced apoptosis in ER‐overexpressing models. E2 and entinostat induced DNA damage as single agents and in combination. These agents synergized against tumor models, offering HDACi as a strategy to enhance efficacy of estrogen therapy.

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Cite

BibTeXRIS
BibTeX
@article{thomas2026pharmacological,
  title = {{Pharmacological chromatin remodeling enhances response to estrogen therapy in ER + breast cancer}},
  author = {Anneka L. Johnson Thomas and Barbara Karakyriakou and Patricia C. Muskus and Alyssa M. Roberts and Justin Rendleman and Alexa Warren and Hanxu Lu and Kimberly A. Birmingham and Malone K. Friedman and Abigail E. Goen and Huijuan Yang and Owen M. Wilkins and Fred W. Kolling and Eugene Demidenko and Julie M. Jorns and Brock C. Christensen and Todd W. Miller},
  journal = {Molecular Oncology},
  year = {2026},
  month = jul,
  doi = {10.1002/1878-0261.70307},
  url = {https://doi.org/10.1002/1878-0261.70307},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Pharmacological chromatin remodeling enhances response to estrogen therapy in ER + breast cancer
AU  - Anneka L. Johnson Thomas
AU  - Barbara Karakyriakou
AU  - Patricia C. Muskus
AU  - Alyssa M. Roberts
AU  - Justin Rendleman
AU  - Alexa Warren
AU  - Hanxu Lu
AU  - Kimberly A. Birmingham
AU  - Malone K. Friedman
AU  - Abigail E. Goen
AU  - Huijuan Yang
AU  - Owen M. Wilkins
AU  - Fred W. Kolling
AU  - Eugene Demidenko
AU  - Julie M. Jorns
AU  - Brock C. Christensen
AU  - Todd W. Miller
PY  - 2026
DA  - 2026/07/17
JO  - Molecular Oncology
DO  - 10.1002/1878-0261.70307
UR  - https://doi.org/10.1002/1878-0261.70307
AB  - Estrogen therapy elicits clinical benefit in ~ 30% of patients with endocrine‐resistant estrogen receptor (ER)‐positive breast cancer, but its mechanism of action and strategies to increase efficacy remain unclear. Estrogen therapy can induce ER transcriptional hyperactivation and DNA damage; we postulated that such damage could be exacerbated by epigenetic dysregulation via inhibition of histone deacetylases (HDACi). We evaluated the effects of 17b‐estradiol and HDACi in three types of ER+ breast cancer models: Cells adapted to growth following long‐term estrogen deprivation; cells engineered to overexpress exogenous ER that confers endocrine resistance; mice bearing endocrine‐resistant patient‐derived xenografts. Assay endpoints included apoptosis, growth, DNA damage, histone post‐translational modification, levels of ER‐regulated transcripts and encoded proteins, cell cycle and replication status, and genome‐wide chromatin accessibility, ER binding, and transcriptional profiles. Entinostat treatment increased histone acetylation and chromatin accessibility. Combination treatment with E2 and entinostat inhibited cell growth and induced apoptosis in ER‐overexpressing models. E2 and entinostat induced DNA damage as single agents and in combination. These agents synergized against tumor models, offering HDACi as a strategy to enhance efficacy of estrogen therapy.
SN  - 1574-7891
SN  - 1878-0261
ER  -