Transactivation of ErbB-2 induced by tumor necrosis factor α promotes NF-κB activation and breast cancer cell proliferation
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Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNFα is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNFα involvement on highly aggressive ErbB-2-overexpressing breast cancer cells. We found that TNFα 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 TNFα-induced c-Src activation. Moreover, TNFα promoted ErbB-2/ErbB-3 heterocomplex formation, Akt activation and NF-κB 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 TNFα-induced NF-κB activation and proliferation. However, the humanized monoclonal antibody anti-ErbB-2 Herceptin could not inhibit TNFα ability to promote breast cancer growth. Interestingly, our work disclosed that TNFα is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. As TNFα 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.
KeywordsErbB-2 TNFα Herceptin c-Src
This work was supported by grants IDB 1728/OC-AR PICT 2006 0211 and PICT 2004 05-25301, both from the National Agency of Scientific Promotion of Argentina, PIP 5391 from the Argentine National Council of Scientific Research (CONICET) and by Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina and by grant KG090250 from the Susan G. Komen for the Cure. The authors wish to thank Dr Alfredo A. Molinolo (NIH, Bethesda, MD) for his constant help and support. We thank Dr C. Lanari for providing the MPA-induced mammary tumor model.
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