Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells

Oncogene. 2000 Dec 14;19(54):6271-6. doi: 10.1038/sj.onc.1204014.

Abstract

ErbB2 can be activated by its own overexpression or be transactivated by the heregulin polypeptide growth factor. Activation of ErbB2 leads to breast cancer cell proliferation, presumably by inducing the activation of extracellular signal-regulated kinases 1,2 (Erk1,2) and Akt. We have previously reported that the growth factor receptor bound protein-2 (Grb2) is required for the proliferation of ErbB2-overexpressing breast cancer cells. We investigated here whether Grb2 protein plays a role in heregulin-stimulated proliferation. Grb2 protein inhibition led to growth inhibition of heregulin-stimulated breast cancer cells, but not Erk1,2 inactivation. These findings are similar to our earlier observations in ErbB2-overexpressing cells. Since Akt can also be activated by heregulin, the effects of Grb2 inhibition on Akt were examined. Akt was inactivated following Grb2 downregulation in heregulin-stimulated breast cancer cells. We then examined the effects of Grb2 downregulation on Akt in ErbB2-overexpressing cells in the absence of heregulin. Similar to heregulin-stimulated cells, Grb2 inhibition also led to Akt inactivation in ErbB2-overexpressing breast cancer cells. Our results indicate that the activation of ErbB2 by heregulin or by its overexpression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Down-Regulation
  • Female
  • GRB2 Adaptor Protein
  • Humans
  • Liposomes / administration & dosage
  • Neuregulin-1 / genetics
  • Neuregulin-1 / pharmacology*
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / physiology*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Liposomes
  • Neuregulin-1
  • Oligodeoxyribonucleotides, Antisense
  • Proteins
  • Proto-Oncogene Proteins
  • Receptor, ErbB-2
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt