c-Jun N-Terminal Kinase Inactivation by Mitogen-Activated Protein Kinase Phosphatase 1 Determines Resistance to Taxanes and Anthracyclines in Breast Cancer

Mitogen-activated protein kinase (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 JNK½. We next assessed MKP-1 expression and JNK½ 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 JNK½ with an adverse impact on relapse of the tumor and overall and disease-free survival. Moreover, MKP-1 and p-JNK½ determinations in 64 locally advanced breast-cancer patients treated with neoadjuvant taxane-based chemotherapy showed an inverse correlation between MKP-1 overexpression (together with JNK½ inhibition) and the pathological 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.