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

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Oncogene (Impact Factor: 8.46). 10/2009; 29(2):174-87. DOI: 10.1038/onc.2009.312
Source: PubMed


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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Available from: Alexandra Lucs
    • "Phosphorylation of these receptors were only found in the peripheral cells of the 3D spheroid, but throughout in 2D culture[78]. Interestingly, phosphorylation of the Tyrosine 1201 (Tyr1201) residue within ErbB2 mediates the apicalbasal polarity of mammary epithelial cell acini in 3D Matrigel culture , whereas Tyr1226/7 phosphorylation activation inhibits apoptosis and induces filling of the acini lumen[151]. These results may, in part, explain the resistance of the cancer cells grown in 3D cultures and the tumors within tissues to therapeutic drugs against these receptors, which could be due to the stock of the inactive receptors buried underneath the outer layers of the cells. "
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    • "Those features are reminiscent of ErbB2-overexpressing DCIS in vivo (Muthuswamy et al., 2001). A recent analysis of ErbB2-mediated transformation indicated the significance of Tyr 1201 phosphorylation for the disruption of apical–basal polarity of MCF10A cells (Lucs et al., 2010). Our laboratory uses a full-length ErbB2 mutant, V659E, as a model of the constitutively activated ErbB2 receptor. "

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