Therapeutic potential of ERK5 targeting in triple negative breast cancer
| Autor: | Alberto Ocaña, María Jesús Ortiz-Ruiz, Sara Zaknoen, Azucena Esparís-Ogando, Francis Burrows, Atanasio Pandiella, Stela Álvarez-Fernández, Tracy Parrott |
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| Přispěvatelé: | Junta de Castilla y León, European Commission, Fundación Ramón Areces, Instituto de Salud Carlos III |
| Rok vydání: | 2014 |
| Předmět: |
kinase inhibitor
Apoptosis Triple Negative Breast Neoplasms Docetaxel Pharmacology Vinorelbine Vinblastine Heterocyclic Compounds 4 or More Rings Mice Random Allocation Breast cancer breast cancer Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Medicine Animals Humans Molecular Targeted Therapy Protein Kinase Inhibitors Triple-negative breast cancer Mitogen-Activated Protein Kinase 7 Cell Proliferation business.industry Kinase Cancer medicine.disease Xenograft Model Antitumor Assays ERK5 Oncology Cancer research Female Taxoids Cisplatin business medicine.drug Research Paper |
| Zdroj: | ResearcherID Oncotarget Digital.CSIC. Repositorio Institucional del CSIC instname Scopus-Elsevier Europe PubMed Central |
| ISSN: | 1949-2553 |
| Popis: | Licensed under a Creative Commons Attribution 3.0 License. Triple negative breast cancers (TNBCs) account for 15% of all breast cancers, and represent one of the most aggressive forms of the disease, exhibiting short relapse-free survival. In contrast to other breast cancer subtypes, the absence of knowledge about the etiopathogenic alterations that cause TNBCs force the use of chemotherapeutics to treat these tumors. Because of this, efforts have been devoted with the aim of incorporating novel therapies into the clinical setting. Kinases play important roles in the pathophysiology of several tumors, including TNBC. Since expression of the MAP kinase ERK5 has been linked to patient outcome in breast cancer, we analyzed the potential value of its targeting in TNBC. ERK5 was frequently overexpressed and active in samples from patients with TNBC, as well as in explants from mice carrying genetically-defined TNBC tumors. Moreover, expression of ERK5 was linked to a worse prognosis in TNBC patients. Knockdown experiments demonstrated that ERK5 supported proliferation of TNBC cells. Pharmacological inhibition of ERK5 with TG02, a clinical stage inhibitor which targets ERK5 and other kinases, inhibited cell proliferation by blocking passage of cells through G1 and G2, and also triggered apoptosis in certain TNBC cell lines. TG02 had significant antitumor activity in a TNBC xenograft model in vivo, and also augmented the activity of chemotherapeutic agents commonly used to treat TNBC. Together, these data indicate that ERK5 targeting may represent a valid strategy against TNBC, and support the development of trials aimed at evaluating the clinical effectiveness of drugs that block this kinase. This work was supported by a grant from the Instituto de Salud Carlos III (PS09/00868) and from the Consejería de Sanidad de la Junta de Castilla y León to AEO. MJOR was supported by Junta de Castilla y León and SAF by the Cancer Center Network Program from the ISCIII (RD06/0020/0041). Support by a grant from the Asociación de Mujeres “Santa Águeda” of Puertollano, Spain is acknowledged. Our Cancer Research Institute, and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces. |
| Databáze: | OpenAIRE |
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