Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity
Open Access
- 12 October 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (2), 174-187
- https://doi.org/10.1038/onc.2009.312
Abstract
Amplification and overexpression of ErbB2 strongly correlates with aggressive breast cancers. A deeper understanding of pathways downstream of ErbB2 signaling that are required for the transformation of human mammary epithelial cells will identify novel strategies for therapeutic intervention in breast cancer. Using an inducible activation of ErbB2 autophosphorylation qsite mutants and the MCF-10A three-dimensional (3D) culture system, we investigated pathways used by ErbB2 to transform the epithelia. We report that ErbB2 induces cell proliferation and loss of 3D organization by redundant mechanisms, whereas it disrupts apical basal polarity and inhibits apoptosis using Tyr 1201 and Tyr 1226/7, respectively. Signals downstream of Tyr 1226/7 were also sufficient to confer paclitaxel resistance. The Tyr 1226/7 binds Shc, and the knockdown of Shc blocks the ability of ErbB2 to inhibit apoptosis and mediate paclitaxel resistance. Tyr 1226/7 is known to activate the Ras/Erk pathway; however, paclitaxel resistance did not correlate with the activation of Erk or Akt, suggesting the presence of a novel mechanism. Thus, our results show that targeting pathways used by ErbB2 to inhibit cell death is a better option than targeting cell proliferation pathways. Furthermore, we identify a novel function for Shc as a regulator of apoptosis and drug resistance in human mammary epithelial cells transformed by ErbB2.Keywords
This publication has 39 references indexed in Scilit:
- ShcA signalling is essential for tumour progression in mouse models of human breast cancerThe EMBO Journal, 2008
- Trastuzumab: triumphs and tribulationsOncogene, 2007
- Controlled Activation of ErbB1/ErbB2 Heterodimers Promote Invasion of Three-Dimensional Organized Epithelia in an ErbB1-Dependent Manner: Implications for Progression of ErbB2-Overexpressing TumorsCancer Research, 2006
- Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 ExpressionClinical Cancer Research, 2006
- The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformationOncogene, 2005
- HER‐2: A biomarker at the crossroads of breast cancer immunotherapy and molecular medicineJournal of Cellular Physiology, 2005
- Mitogen-activated protein kinases in apoptosis regulationOncogene, 2004
- HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cellsOncogene, 2003
- Peptide–Surface Association: The Case of PDZ and PTB DomainsCell, 1996
- Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/ neu OncogeneScience, 1987