HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer
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Accepted Version
Date
2021-07-10
Authors
Clements, Miranda E.
Holtslander, Lauren
Edwards, Courtney
Todd, Vera
Dooyema, Samuel D. R.
Bullock, Kennady
Bergdorf, Kensey
Zahnow, Cynthia A.
Connolly, Roisin M.
Johnson, Rachelle W.
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature Switzerland AG
Published Version
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.
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Keywords
HDACi , Dormancy , Breast cancer
Citation
Clements, M. E., Holtslander, L., Edwards, C., Todd, V., Dooyema, S. D., Bullock, K., Bergdorf, K., Zahnow, C. A., Connolly, R. M. and Johnson, R. W. (2021) ‘HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer’, Oncogene, 40(34), pp.5314-5326. doi: 10.1038/s41388-021-01931-1
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© 2021, the Authors, under exclusive licence to Springer Nature B.V. This is a post-peer-review, pre-copyedit version of an article published in Oncogene. The final authenticated version is available online at: https://doi.org/10.1038/s41388-021-01931-1