Transactivation of ErbB-2 Induced by Tumor Necrosis Factor Alpha Promotes NF-KB Activation and Breast Cancer Cell Proliferation

RIVAS MA ; TKACH M; PROIETTI CJ; BEGUELIN W; DIAZ FALQUE MC; ROSEMBLIT C; CHARREAU EH; ELIZALDE PV; SCHILLACI R

Holderness, New Hampshire

Congreso; Gordon Research Conference Hormone Action in Development & Cancer; 2009

Gordon research Conferences

Transactivation of ErbB-2 Induced by Tumor Necrosis Factor Alpha Promotes NF-kB Activation and Breast Cancer Cell Proliferation Martín A. Rivas, Mercedes Tkach, Cecilia J. Proietti, Wendy Béguelin, M. Celeste Díaz Flaqué, Cinthia Rosemblit, Eduardo H. Charreau, Patricia V. Elizalde, Roxana Schillaci BACKGROUND: ErbB-2 is an orphan receptor belonging to the family of type I tyrosine kinase receptors which signals by forming heterodimers with epidermal growth factor receptor (EGFR), ErbB-3 and ErbB-4 in response to ligands including heregulins. After ligand binding, all ErbB receptors are phosphorylated, serving as docking sites for the recruitment of cytoplasmic adaptor proteins, initiating signaling cascades that control multiple cellular processes. Overexpression of ErbB-2 has been found in nearly 30% of breast cancer patients. These tumors tend to be more aggressive and the disease has poor prognosis, for which ErbB-2 has been intensely pursued as a therapeutic target. These studies have led to the development of two major classes of anti-ErbB-2 therapies, used at present in clinical practice: monoclonal antibodies which bind the extracellular region of the receptor and small-molecule tyrosine kinase inhibitors. However, only 30% of the patients treated with the monoclonal antibody ErbB-2-directed trastuzumab (Herceptin?) respond to the treatment. An important reason for this is that other tumor-cell alterations may influence the response to ErbB-2-targeted inhibitors (Hynes and Lane, 2005). Thus, understanding the mechanism by which ErbB-2 can be activated through non-classical receptors and ligands is relevant to design a new therapeutic approach and to predict patients´ response to treatment. Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine. It is now widely accepted that TNFα, acting locally, is able to induce the growth of certain tumor types such as ovary and breast cancer. TNFα has been shown to be produced by malignant or host cells in the tumor microenvironment of human infiltrating breast cancer and to be associated with increasing malignancy. In particular, we have recently demonstrated that TNFa induces in vitro proliferation of the murine mammary tumor C4HD through a mechanism which requires activation of p42/p44 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), Akt and NF-kB transcriptional activation. C4HD tumor belongs to an experimental model of hormonal carcinogenesis in which medroxyprogesterone acetate induced mammary adenocarcinomas in Balb/c mice. In addition, we have shown that TNFa also supports C4HD growth in vivo. As ErbB-2 overexpression is linked to NF-kB activation  and ErbB-2 plays a critical role in C4HD proliferation  we wondered whether an interaction between TNFα and ErbB-2 could exist. Several groups have so far shown transactivation of EGFR by TNFα in human airway epithelial cells, tracheal smooth muscle cells and mammary epithelial cells. In contrast, there are no reports demonstrating TNFα´s ability to transactivate ErbB-2 in breast cancer. Objective: To study the cross-talk between TNFα and ErbB2 signaling pathways in breast cancer cells and the functional implications of this interaction. This is the first demonstration of ErbB-2 transactivation by TNFα in breast cancer cells, which may be one of the mechanisms by which ErbB-2-overexpressing tumors show resistance to anti ErbB-2 monoclonal antibodies therapy.