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

Tumor necrosis factor alpha (TNF alpha) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNF alpha is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNF alpha involvement on highly aggressive ErbB-2-overexpressing breast cancer cells. We found that TNF alpha 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 TNF alpha-induced c-Src activation. Moreover, TNF alpha promoted ErbB-2/ErbB-3 heterocomplex formation, Akt activation and NF-kappa B 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 TNF alpha-induced NF-kappa B activation and proliferation. However, the humanized monoclonal antibody anti-ErbB-2 Herceptin could not inhibit TNF alpha ability to promote breast cancer growth. Interestingly, our work disclosed that TNF alpha is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. As TNF alpha 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.