Transactivation of ErbB-2 induced by tumor necrosis factor α promotes NF-κB activation and breast cancer cell proliferation

Autor: Cecilia J. Proietti, Martín A. Rivas, Patricia V. Elizalde, Wendy Béguelin, Mercedes Tkach, Eduardo H. Charreau, Cinthia Rosemblit, Roxana Schillaci
Rok vydání: 2009
Předmět:
Zdroj: Breast Cancer Research and Treatment. 122:111-124
ISSN: 1573-7217
0167-6806
DOI: 10.1007/s10549-009-0546-3
Popis: Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNFalpha is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNFalpha involvement on highly aggressive ErbB-2-overexpressing breast cancer cells. We found that TNFalpha induces ErbB-2 phosphorylation in mouse breast cancer C4HD cells and in the human breast cancer cell lines SK-BR-3 and BT-474. ErbB-2 phosphorylation at Tyr877 residue was mediated by TNFalpha-induced c-Src activation. Moreover, TNFalpha promoted ErbB-2/ErbB-3 heterocomplex formation, Akt activation and NF-kappaB transcriptional activation. Inhibition of ErbB-2 by addition of AG825, an epidermal growth factor receptor/ErbB-2-tyrosine kinase inhibitor, or knockdown of ErbB-2 by RNA interference strategy, blocked TNFalpha-induced NF-kappaB activation and proliferation. However, the humanized monoclonal antibody anti-ErbB-2 Herceptin could not inhibit TNFalpha ability to promote breast cancer growth. Interestingly, our work disclosed that TNFalpha is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. As TNFalpha has been shown to be present in the tumor microenvironment of a significant proportion of human infiltrating breast cancers, our findings would have clinical implication in ErbB-2-positive breast cancer treatment.
Databáze: OpenAIRE
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