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

Holderness, USA

Conferencia; Gordon Research Conference Hormone Action in Development & Cancer.; 2009

BACKGROUND: ErbB-2 is an orphan receptor belonging to the family of type I tyrosinekinase receptors which signals by forming heterodimers with epidermal growth factorreceptor (EGFR), ErbB-3 and ErbB-4 in response to ligands including heregulins. Afterligand binding, all ErbB receptors are phosphorylated, serving as docking sites for therecruitment of cytoplasmic adaptor proteins, initiating signaling cascades that controlmultiple cellular processes. Overexpression of ErbB-2 has been found in nearly 30% ofbreast cancer patients. These tumors tend to be more aggressive and the disease has poorprognosis, for which ErbB-2 has been intensely pursued as a therapeutic target. Thesestudies have led to the development of two major classes of anti-ErbB-2 therapies, usedat present in clinical practice: monoclonal antibodies which bind the extracellular regionof the receptor and small-molecule tyrosine kinase inhibitors. However, only 30% of thepatients treated with the monoclonal antibody ErbB-2-directed trastuzumab(Herceptin™) respond to the treatment. An important reason for this is that other tumorcellalterations may influence the response to ErbB-2-targeted inhibitors (Hynes andLane, 2005). Thus, understanding the mechanism by which ErbB-2 can be activatedthrough non-classical receptors and ligands is relevant to design a new therapeuticapproach 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, isable to induce the growth of certain tumor types such as ovary and breast cancer. TNFαhas been shown to be produced by malignant or host cells in the tumor microenvironmentof human infiltrating breast cancer and to be associated with increasing malignancy. Inparticular, we have recently demonstrated that TNFa induces in vitro proliferation of themurine mammary tumor C4HD through a mechanism which requires activation ofp42/p44 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK),Akt and NF-kB transcriptional activation. C4HD tumor belongs to an experimental modelof hormonal carcinogenesis in which medroxyprogesterone acetate induced mammaryadenocarcinomas in Balb/c mice. In addition, we have shown that TNFa also supportsC4HD growth in vivo. As ErbB-2 overexpression is linked to NF-kB activation andErbB-2 plays a critical role in C4HD proliferation we wondered whether an interactionbetween TNFα and ErbB-2 could exist. Several groups have so far shown transactivationof EGFR by TNFα in human airway epithelial cells, tracheal smooth muscle cells andmammary epithelial cells. In contrast, there are no reports demonstrating TNFα´s abilityto transactivate ErbB-2 in breast cancer. Objective: To study the cross-talk betweenTNFα and ErbB2 signaling pathways in breast cancer cells and the functionalimplications of this interaction. This is the first demonstration of ErbB-2 transactivationby 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.