Alteration of DNMT1/DNMT3A by eribulin elicits global DNA methylation changes with potential therapeutic implications...

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options.
• Eribulin, a chemotherapeutic agent, is approved for advanced breast cancer and known to induce epigenetic modifications.
• Understanding eribulin's impact on TNBC epigenetics is crucial for developing novel treatment strategies.

Approach:

• Investigated genome-scale DNA methylation patterns in TNBC cells following repeated eribulin treatment.
• Analyzed changes in transcription factor binding, specifically at ZEB1 sites.
• Examined the expression of key epigenetic modifiers, including DNMT1, TET1, and DNMT3A/B.
• Validated findings in primary human TNBC tumors.

Key Points:

• Eribulin treatment induced significant changes in DNA methylation patterns in TNBC persister cells.
• Eribulin affected transcription factor binding and regulated critical cellular pathways like ERBB and VEGF signaling.
• The drug altered the expression of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in TNBC cells and human tumors.

Conclusions:

• Eribulin modulates DNA methylation in TNBC by altering the expression of epigenetic modifiers.
• These findings highlight the potential clinical utility of eribulin in TNBC therapy.
• Eribulin's epigenetic effects provide a mechanistic basis for its efficacy in treating TNBC.