期刊
MOLECULAR CANCER RESEARCH
卷 17, 期 10, 页码 2063-2076出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0040
关键词
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资金
- Spanish Ministerio de Ciencia, Innovacion y Universidades, Agencia Estatal de Investigacion (AEI) [SAF2008-01975, SAF2011-22893, SAF2014-55997-R, SAF2017-86117-R, ISCIII PIE13/00022]
- European Regional Development Fund. ERDF, a way to build Europe
- Susan Komen Foundation [CCR13262449]
- ERC [LS4-682935]
- Instituto de Salud Carlos III [PI13/01718]
- Banco Bilbao Vizcaya Argentaria (BBVA) Foundation
- Sociedad Espanola de Oncologia Medica (SEOM) grant
- MICINN
- FI programme of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia
- European Social Fund (ESF), Investing in your future
- GHD-pink via the FERO Foundation
- Breast Cancer Research Foundation [BCRF-17-008]
- Susan G. Komen Foundation
- V Foundation
- NIH/NCI [U54CA224076]
- BCM Breast Cancer SPORE [P50 CA186784]
- BCM Cancer Center grant [P30 CA125123]
- ISCIII [JR17/00016]
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.
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