Development of Paclitaxel Resistance in Triple-Negative Breast Cancer Is Associated with Extensive DNA Methylation Changes That Are Partially Reversed by Decitabine

AimsChemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study investigated whether resistance development is associated with DNA methylation changes and assessed the potential of the DNA methyltransferase inhibitor decitabine (DAC) to reverse these alterations and enhance chemosensitivity. MethodsMolecular profiling and functional assays were used to characterize paclitaxel-(PAC) and doxorubicin-(DOX) resistant BC cell lines derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive trastuzumab-resistant (JIMT-1) models. Therapeutic responses to DAC and DOX, alone and in combination, were evaluated in MDA-MB-231 xenografts. DNA methylation-associated gene expression changes were analyzed through integrative approaches. ResultsChemoresistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and extensive genomic alterations. Upregulation of RELB and downregulation of PPARG were observed across several resistant cell lines, while CDA expression was uniformly elevated in all DOX-resistant models. PAC-resistant xenografts displayed widespread methylation and transcriptomic reprogramming. DAC treatment partially restored aberrant methylation patterns and increased Ki-67 expression, potentially enhancing DOX responsiveness. ConclusionsChemoresistance in BC involves extensive genomic and epigenetic reprogramming. DAC modulates methylation and tumor phenotype but is insufficient to overcome resistance, highlighting the need for rational combination strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/655519v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8c6b06org.highwire.dtl.DTLVardef@c67805org.highwire.dtl.DTLVardef@1f1b282org.highwire.dtl.DTLVardef@feb046_HPS_FORMAT_FIGEXP M_FIG C_FIG