Activation of ErbB2 by Overexpression or by Transmembrane Neuregulin Results in Differential Signaling and Sensitivity to Herceptin
- 1 August 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (15) , 6801-6810
- https://doi.org/10.1158/0008-5472.can-04-4023
Abstract
The ligands of the epidermal growth factor family and their receptors, the ErbB proteins, have been linked to the development of different types of cancer. Particular attention has focused on ErbB2, whose activation may occur by receptor overexpression or by ligand-induced oligomerization with other ErbB receptors. Whether these two modes of ErbB2 activation cause the same biological responses is unknown. Here, we uncovered important differences in the signaling, proliferation rates, and the response to anti-ErbB2 antibodies when comparing MCF7 cells expressing the ligand neuregulin, to MCF7 cells overexpressing ErbB2. Expression of neuregulin caused higher proliferation than ErbB2 overexpression. Transmembrane neuregulin expression was accompanied by constitutive activation of ErbB2, ErbB3, and ErbB4 receptors. ErbB2 overexpression caused tyrosine phosphorylation of ErbB2, whereas ErbB3 and ErbB4 were only slightly tyrosine phosphorylated. Autocrine transmembrane neuregulin also caused constitutive activation of several signaling pathways, such as the Erk1/2, Erk5, and Akt routes, which have been linked to breast cancer cell proliferation. Interestingly, expression of neuregulin increased p21 levels and this was required for the proliferation of MCF7 cells. Treatment with the anti-ErbB2 receptor antibody Herceptin had an inhibitory effect on proliferation only in cells expressing neuregulin but not on cells overexpressing ErbB2, and its inhibitory activity was accompanied by a decrease in p21. These results suggest that Herceptin may also be of help in the treatment of tumors in which neuregulin feeds the tumoral tissue.Keywords
This publication has 34 references indexed in Scilit:
- Co‐expression of neuregulins 1, 2, 3 and 4 in human breast cancerThe Journal of Pathology, 2004
- The Cyclin-dependent Kinase Inhibitor p21CIP/WAF Is a Positive Regulator of Insulin-like Growth Factor I-induced Cell Proliferation in MCF-7 Human Breast Cancer CellsPublished by Elsevier ,2003
- The ErbB receptors and their role in cancer progressionExperimental Cell Research, 2003
- Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancerOncogene, 2003
- Erk5 Participates in Neuregulin Signal Transduction and Is Constitutively Active in Breast Cancer Cells Overexpressing ErbB2Molecular and Cellular Biology, 2002
- Differential Shedding of Transmembrane Neuregulin Isoforms by the Tumor Necrosis Factor-α-Converting EnzymeMolecular and Cellular Neuroscience, 2000
- NEW EMBO MEMBERS' REVIEW: The ErbB signaling network: receptor heterodimerization in development and cancerThe EMBO Journal, 2000
- Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cellsOncogene, 1999
- ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signalingThe EMBO Journal, 1997
- Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/ neu OncogeneScience, 1987