Alteration of DNA Methyltransferases by Eribulin Elicits Broad DNA Methylation Changes with Potential Therapeutic Implications for Triple-Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options. Eribulin, a chemotherapeutic drug, induces epigenetic changes in cancer cells, suggesting a unique mechanism of action. Materials & methods: MDA-MB 231 cells were treated with eribulin and paclitaxel, and the samples from 53 patients treated with neoadjuvant eribulin were compared with those from 14 patients who received the standard-of-care treatment using immunohistochemistry. Results: Eribulin treatment caused significant DNA methylation changes in drug-tolerant persister TNBC cells, and it also elicited changes in the expression levels of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in vitro and in primary TNBC tumors. Conclusion: These findings provide new insights into eribulin’s mechanism of action and potential biomarkers for predicting TNBC treatment response.

Keywords::

• breast cancer
• chemotherapy
• DNA methylation
• epigenetic
• epithelial-to-mesenchymal transition

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0339

Author contributions

The project was conceived and designed by M Bagheri and M Lee. The methodology was developed by M Bagheri, M Lee, K Muller, T Miller and B Christensen. Data acquisition was carried out by M Bagheri and M Lee. Data analysis and interpretation were performed by M Bagheri, M Lee, K Muller, T Miller and B Christensen. The manuscript was written, reviewed and/or edited by M Bagheri, M Lee, K Muller, T Miller, B Christensen and D Pattabiraman. T Miller, B Christensen and D Pattabiraman supervised the study.

Acknowledgments

The authors thank O Wilkins at the Center for Quantitative Biology at Dartmouth for providing code for statistical analysis. They also thank the Dartmouth Cancer Center Genomics and Molecular Biology Shared Resource (RRID: SCR_021293) and Pathology Shared Resource (RRID: SCR_023479). Funding and resources for the shared resources were supported in part by a core grant (P30CA023108; Dartmouth Cancer Center).

Financial disclosure

Research reported in this publication was supported through the Geisel School of Medicine at Dartmouth’s Center for Quantitative Biology through a grant from the NIGMS Award P20GM130454, an NIH S10 (S10OD025235) grant, and funding from The Elmer R Pfefferkorn & Allan U Munck Education and Research Fund at Dartmouth (D Pattabiraman). This work was supported by funding from METAvivor (D Pattabiraman) and NIH (R00CA201574 [D Pattabiraman], R01CA267691 [D Pattabiraman and T Miller] and R01CA216265, R01CA253976 [B Christensen]). This study received partial support through a Sponsored Research Agreement from Eisai, Inc. to D Pattabiraman; the authors and Eisai, Inc. declare no competing interests related to this study. B Christensen is an advisor to Guardant Health, which had no role in this research. All other authors report that they have no conflicts of interest to declare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

This study was partially supported by Eisai Inc. through a Sponsored Research Agreement, which was reviewed and approved by Eisai Inc. The authors and Eisai Inc. declare no competing interests related to the study. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

SOLTI-1007-NeoEribulin was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol was approved by independent ethics committees at each center and the Agencia Española de Medicamentos y Productos Sanitarios. All patients provided written informed consent. Specimens from Dartmouth-Hitchcock Medical Center were obtained through clinically indicated procedures for diagnostic purposes. Use of these specimens for this research was approved the Dartmouth Health Human Research Protection Program (STUDY02000731).

Data sharing statement

The raw and analyzed data were submitted to the Gene Expression Omnibus with the accession number GSE234881.

Additional information

Funding

Research reported in this publication was supported through the Geisel School of Medicine at Dartmouth’s Center for Quantitative Biology through a grant from the NIGMS National Institute of General Medical Sciences Award P20GM130454, an NIH National Institutes of Health S10 (S10OD025235) grant, and funding from The Elmer R Pfefferkorn & Allan U Munck Education and Research Fund at Dartmouth (D Pattabiraman). This work was supported by funding from METAvivor (D Pattabiraman) and NIH National Institutes of Health (R00CA201574 [D Pattabiraman], R01CA267691 [D Pattabiraman and T Miller] and R01CA216265, R01CA253976 [B Christensen]). This study received partial support through a Sponsored Research Agreement from Eisai, Inc. to D Pattabiraman; the authors and Eisai, Inc. declare no competing interests related to this study. B Christensen is an advisor to Guardant Health, which had no role in this research. All other authors report that they have no conflicts of interest to declare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.