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Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity

Oncogene volume 29, pages 174–187 (2010)Cite this article

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.

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Acknowledgements

We thank the members of the Muthuswamy Laboratory for critical discussions and comments on the paper. This work was supported by CA098830 and CA105388 Grants from NCI, DOD BC075024 from DOD Breast Cancer Research Program, Rita Allen Foundation, FACT foundation and Lee K Margaret Lau Chair in Breast Cancer Research to SKM and DAMD17-03-1-0196 from DOD Breast Cancer Research Program to AL.

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Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    A V Lucs & S K Muthuswamy

  2. Goodman Cancer Center, McGill University, Montreal, Quebec, Canada

    W J Muller

  3. Department of Microbiology and Molecular Genetics, Stony Brook University, Stony Brook, NY, USA

    A V Lucs & S K Muthuswamy

  4. Department of Medical Biophysics, Ontario Cancer Institute, Campbell Family Institute for Breast Cancer Research, University of Toronto, Ontario, Canada

    S K Muthuswamy

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  1. A V Lucs
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Correspondence to S K Muthuswamy.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lucs, A., Muller, W. & Muthuswamy, S. Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity. Oncogene 29, 174–187 (2010). https://doi.org/10.1038/onc.2009.312

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