期刊
MOLECULAR CANCER THERAPEUTICS
卷 15, 期 11, 页码 2780-2790出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0920
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资金
- Spanish Ministry of Economy and Competitiveness (MINECO) [PI12/01552, PI12/00680, PI12/01421]
- Ministry of Health (Cancer Network)
- Community of Madrid [S2010/BMD-2344]
- Government of Catalonia [2014/SGR/740]
- MINECO [RD12/0036/0021, RD12/0036/0051, RD12/0036/0070]
- Biobanks initiative
- intensification program ISCIII/FEDER
- Fundacion Conchita Rabago de Jimeenez Diaz grants
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. (C) 2016 AACR.
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