Bagheri Meisam, Lee Min Kyung, Muller Kristen E, Miller Todd W, Pattabiraman Diwakar R, Christensen Brock C
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766.
Dartmouth Cancer Center, Lebanon, NH, 03756.
bioRxiv. 2023 Jun 10:2023.06.09.544426. doi: 10.1101/2023.06.09.544426.
Triple-negative breast cancer (TNBC) is an aggressive disease subtype with limited treatment options. Eribulin is a chemotherapeutic approved for the treatment of advanced breast cancer that has been shown to elicit epigenetic changes. We investigated the effect of eribulin treatment on genome-scale DNA methylation patterns in TNBC cells. Following repeated treatment, The results showed that eribulin-induced changes in DNA methylation patterns evident in persister cells. Eribulin also affected the binding of transcription factors to genomic ZEB1 binding sites and regulated several cellular pathways, including ERBB and VEGF signaling and cell adhesion. Eribulin also altered the expression of epigenetic modifiers including DNMT1, TET1, and DNMT3A/B in persister cells. Data from primary human TNBC tumors supported these findings: DNMT1 and DNMT3A levels were altered by eribulin treatment in human primary TNBC tumors. Our results suggest that eribulin modulates DNA methylation patterns in TNBC cells by altering the expression of epigenetic modifiers. These findings have clinical implications for using eribulin as a therapeutic agent.
三阴性乳腺癌（TNBC）是一种侵袭性疾病亚型，治疗选择有限。艾日布林是一种被批准用于治疗晚期乳腺癌的化疗药物，已被证明可引发表观遗传变化。我们研究了艾日布林治疗对TNBC细胞全基因组DNA甲基化模式的影响。经过重复治疗，结果表明艾日布林诱导的DNA甲基化模式变化在持续存在的细胞中明显。艾日布林还影响转录因子与基因组ZEB1结合位点的结合，并调节多种细胞途径，包括ERBB和VEGF信号传导以及细胞粘附。艾日布林还改变了持续存在的细胞中表观遗传修饰因子的表达，包括DNMT1、TET1和DNMT3A/B。来自原发性人类TNBC肿瘤的数据支持了这些发现：在人类原发性TNBC肿瘤中艾日布林治疗改变了DNMT1和DNMT3A的水平。我们的结果表明，艾日布林通过改变表观遗传修饰因子的表达来调节TNBC细胞中的DNA甲基化模式。这些发现对于将艾日布林用作治疗药物具有临床意义。
