c-Jun N-Terminal Kinase Inactivation by Mitogen-Activated Protein Kinase Phosphatase 1 Determines Resistance to Taxanes and Anthracyclines in Breast Cancer.
MAPK phosphatase-1 (MKP-1) is overexpressed during malignant transformation of the breast in many patients, and it is usually associated with chemoresistance through interference with JNK-driven apoptotic pathways. Although the molecular settings of the mechanism have been documented, details about the contribution of MKP-1 to the failure of chemotherapeutic interventions are unclear. Transient overexpression of MKP-1 and treatment with JNK-modulating agents in breast carcinoma cells confirmed the mediation of MKP-1 in the resistance to taxanes and anthracyclines in breast cancer, through the inactivation of JNK1/2. We next assessed MKP-1 expression and JNK1/2 phosphorylation status in a large cohort of samples from 350 early breast cancer patients treated with adjuvant anthracycline-based chemotherapy. We detected that MKP-1 overexpression is a recurrent event predominantly linked to dephosphorylation of JNK1/2 with an adverse impact on relapse of the tumor and overall and disease-free survival. Moreover, MKP-1 and p-JNK1/2 determinations in 64 locally advanced breast cancer patients treated with neoadjuvant taxane-based chemotherapy showed an inverse correlation between MKP-1 overexpression (together with JNK1/2 inhibition) and the pathologic response of the tumors. Our results emphasize the importance of MKP-1 as a potential predictive biomarker for a subset of breast cancer patients with worse outcome and less susceptibility to treatment. Mol Cancer Ther; 15(11); 2780-90. ©2016 AACR.
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Raúl
R
Rincón
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Sandra
S
Zazo
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Cristina
C
Chamizo
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Rebeca
R
Manso
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Paula
P
González-Alonso
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Ester
E
Martín-Aparicio
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Díaz, Madrid, Spain.
Ion
I
Cristóbal
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain.
Carmen
C
Cañadas
"Alberto Sols" Biomedical Research Institute CSIC-UAM, Madrid, Spain.
Rosario
R
Perona
Institute of Health Research INCLIVA, Valencia, Spain.
Ana
A
Lluch
Institute of Health Research INCLIVA, Valencia, Spain.
Pilar
P
Eroles
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Díaz, Madrid, Spain.
Jesús
J
García-Foncillas
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
Joan
J
Albanell
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
Ana
A
Rovira
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain. JMadoz@fjd.es frojo@fjd.es.
Juan
J
Madoz-Gúrpide
Pathology Department, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain. JMadoz@fjd.es frojo@fjd.es.
Federico
F
Rojo
D018943:Anthracyclines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D043823:Taxoids / Q000494:pharmacology*
D018943:Anthracyclines; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D043823:Taxoids; D048031:JNK Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1