HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer

Miranda E. Clements, Lauren Holtslander, Courtney Edwards, Vera Todd, Samuel D.R. Dooyema, Kennady Bullock, Kensey Bergdorf, Cynthia A. Zahnow, Roisin M. Connolly, Rachelle W. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells. HDACi slowed breast cancer cell proliferation and reduced primary tumor growth. Primary breast tumors from HDACi-treated patients had increased LIFR levels and reduced proliferation rates compared to pre-treatment levels. Recent Phase II clinical trial data studying entinostat and azacitidine in metastatic breast cancer revealed that induction of several pro-dormancy genes post-treatment was associated with prolonged patient survival. Together, these findings suggest HDACi as a potential therapeutic avenue to promote dormancy, prevent recurrence, and improve patient outcomes in breast cancer.

Original languageEnglish (US)
Pages (from-to)5314-5326
Number of pages13
JournalOncogene
Volume40
Issue number34
DOIs
StatePublished - Aug 26 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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