1. c-Jun N-Terminal Kinase Inactivation by Mitogen-Activated Protein Kinase Phosphatase 1 Determines Resistance to Taxanes and Anthracyclines in Breast Cancer.
- Author
-
Rincón R, Zazo S, Chamizo C, Manso R, González-Alonso P, Martín-Aparicio E, Cristóbal I, Cañadas C, Perona R, Lluch A, Eroles P, García-Foncillas J, Albanell J, Rovira A, Madoz-Gúrpide J, and Rojo F
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Apoptosis drug effects, Biomarkers, Tumor, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms mortality, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cluster Analysis, Dual Specificity Phosphatase 1 genetics, Female, Gene Expression, Gene Expression Profiling, Humans, Kaplan-Meier Estimate, Neoplasm Grading, Prognosis, Proportional Hazards Models, Recurrence, Anthracyclines pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, Drug Resistance, Neoplasm, Dual Specificity Phosphatase 1 metabolism, JNK Mitogen-Activated Protein Kinases metabolism, Taxoids pharmacology
- Abstract
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., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF