c-Jun N-terminal kinase inactivation by mitogen-activated protein kinase phosphatase 1 determines resistance to taxanes and anthracyclines in breast cancer
A partir d'échantillons tumoraux prélevés sur 350 patientes atteintes d'un cancer du sein de stade précoce et 64 patientes atteintes d'un cancer du sein de stade localement avancé, cette étude identifie une association entre une surexpression de la phosphatase MKP-1 et la résistance à une chimiothérapie adjuvante à base d'anthracycline ou à une chimiothérapie néoadjuvante à base de taxane
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.
Molecular Cancer Therapeutics , résumé, 2015