The altered transcriptome and DNA methylation profiles of docetaxel resistance in breast cancer PDX models

Taxanes are standard therapy in clinical practice for metastatic breast cancer (BC), however, primary or acquired chemoresistance are a common cause of mortality. BC patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA-methylation patterns have been associated to different BC subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel-resistance mechanisms, we perform genome-wide DNA-methylation in BC PDX models, including luminal and triple-negative BC (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short term docetaxel treatment. We found that DNA-methylation patterns from BC PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA-methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA-methylation signature of resistance able to segregate TNBC chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA-methylation and transcriptional changes identified between docetaxel-sensitive and resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC. Implications: Subtype-specific DNA-methylation patterns are maintained in BC PDX models. While no global methylation changes were found, we uncovered differentially DNA-methylated and expressed genes/pathways associated to the emergence of docetaxel resistance in TNBC.