The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models

Abstract

Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer 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 breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (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 profiles from breast cancer 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 based on 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 breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC.

Genome-wide DNA methylation analysis of breast cancer MCF-7 / Taxol cells with MeDIP-Seq

“…These results indicated that DNA methylation patterns were different between the two groups of cells. Moreover, many studies have shown that the methylation patterns of breast cancer resistant cells and sensitive cells are different [20][21][22]. This information also proves the reliability of our research results.…”

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells

“…Recent studies have reported the role of epigenetic changes in drug resistance, including DNA methylation [ 31 ], histone modifications [ 16 ], and chromatin accessibility [ 13 ]. We next hypothesized that chromatin accessibility is involved in anlotinib resistance.…”

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

“…An open question remains regarding how accurately these PDXs reproduce the metastatic behavior of the patient's tumor, as well as more general metastatic characteristics associated with breast cancer subtype. Although considerable evidence exists that these PDXs can produce CTCs and generate micro-and macroscopic metastatic lesions within several distant sits in the mouse (41,(43)(44)(45), a full credentialization of the metastatic propensity of this vast tissue resource remains an evolving collective task. Given that ER+ cancers typically exhibit longer latency and a proclivity to metastasize to bone, the development of humanized mouse models in which breast cancer PDXs metastasize to human bone implants has created a highly reliable system to interrogate late-stage metastasis to the bone (46).…”