Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity.
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.
Lucs
A V
AV
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Muller
W J
WJ
Muthuswamy
S K
SK
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004351:Drug Resistance / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D014443:Tyrosine