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Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

Oncogene volume 19, pages 6102–6114 (2000)Cite this article

Abstract

Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21Waf1 plays an important role in evasion from apoptosis. These recent findings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance.

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Acknowledgements

We thank Drs David Givol, Doron Ginzberg and Patrick Humbert for critical comments, and Mr Fred Meadows for proof-reading the manuscript. Due to space limitation, many original and important studies have not been cited directly, but rather through reviews. Our laboratory is supported by grants from the National Cancer Institute of the US National Institute of Health, Genetech Inc., The Israel Science Foundation and the US Department of Defense Breast Cancer Research Program.

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  1. Department of Biological Regulation, the Weizmann Institute of Science, 76100, Rehovot, Israel

    Daniel Harari & Yosef Yarden

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Harari, D., Yarden, Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19, 6102–6114 (2000). https://doi.org/10.1038/sj.onc.1203973

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