Available online 2 January 2026, 101350

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Chemoresistant BC cells exhibit a slow-cycling phenotype and reduced tumorigenicity

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Drug resistance is accompanied by broad CNVs and small nucleotide alterations

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Paclitaxel-resistant TNBC xenografts show extensive DNA methylation reprogramming

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DAC reduces abberant DNA methylation and partially improves chemosensitivity

AbstractAims

Chemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study aimed to investigate the role of DNA methylation in this complex process and evaluate the potential of the DNA methyltransferase inhibitor decitabine (DAC) in restoring chemosensitivity.

Methods

Paclitaxel (PAC)- and doxorubicin (DOX)- resistant BC cell lines were derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive (JIMT-1) models and characterized by molecular profiling and functional assays. The therapeutic effects of DAC and DOX were assessed in MDA-MB-231 xenografts, and integrative analyses of DNA methylation and gene expression identified pathways associated with resistance. Follow-up analyses were performed in PAC-resistant MAS98.12 patient-derived xenografts (PDX) and in clinical samples from the NeoAva trial (NCT00773695).

Results

Resistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and widespread genomic alterations. PAC-resistant xenografts showed extensive methylation and transcriptomic reprogramming, partly restored by DAC, which increased Ki-67 expression and enhanced DOX responsiveness. In contrast, PDX tumors displayed less pronounced changes, predominantly hypomethylation, indicating distinct resistance mechanisms. Importantly, xenograft-derived CpG signatures stratified NeoAva patients by treatment response.

Conclusions

Chemoresistance in BC involves extensive genomic and epigenetic remodeling. Although DAC can modulate methylation and tumor phenotype, rational drug combinations will be required to overcome resistance.

Keywords

DNA methylation

Breast cancer

Chemoresistance

Decitabine

Combination therapy

Data AvailabilityTranscriptomic data are available at Gene Expression Omnibus under accession GSE293933. Whole exome sequencing data were submitted to the Sequence Read Archive under accession PRJNA1250986. Additional data generated or analyzed during this study are included in this article and its Supplementary Material files.

© 2026 The Author(s). Published by Elsevier Ltd.