AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

Oncogene. 2002 May 16;21(22):3532-40. doi: 10.1038/sj.onc.1205438.

Abstract

Amplification or overexpression of the HER-2/neu gene in breast cancers is associated with aggressive behavior and resistance to therapeutic regimens. The molecular mechanisms that contribute to therapeutic resistance/survival of HER-2/neu-overexpressing tumor cells have not been well defined. To determine if phosphatidylinositol 3-kinase/AKT signaling contributes to cell survival in HER-2/neu-positive breast cancers, we performed immunohistochemical analyses to evaluate expression of HER-2/neu and AKT in a series of 52 breast carcinomas. Elevated expression of HER-2/neu was found to correlate with overexpression of AKT2 protein and activation of AKT kinase. HER-2/neu-overexpressing breast cancer cell lines were resistant to apoptosis induced by UV treatment and hypoxia, which was suppressed in the presence of the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin, indicating a link between AKT activation and stress resistance in HER-2/neu-overexpressing cells. These observations suggest that AKT signaling augments resistance to stress-induced apoptosis in breast cancer cells overexpressing HER-2/neu.

Publication types

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

MeSH terms

  • Androstadienes / pharmacology
  • Apoptosis*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma / enzymology
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Hypoxia
  • Cell Survival
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Morpholines / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, ErbB-2 / analysis*
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation*
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Receptor, ErbB-2
  • AKT1 protein, human
  • AKT2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin