The HER2/Grb2/Akt pathway regulates the DNA binding activity of AP-1 in breast cancer cells

Oncol Rep. 2004 Oct;12(4):903-8.

Abstract

We showed that the HER2/Grb2/Akt pathway induces all-trans retinoic acid (ATRA) resistance in breast cancer cells by suppressing the DNA binding activity of retinoic acid receptors (RAR). AP-1 activation was shown to induce ATRA resistance. Here, we determined whether AP-1 binding activity is correlated with ATRA resistance in HER2-overexpressing cells. Inhibition of HER2/Grb2/Akt decreased AP-1 binding activity in HER2-transfected cells, but increased AP-1 activity in cells that are naturally HER2-overexpressing. Since HER2/Grb2/Akt inhibition sensitized both cell types to ATRA, our results indicate that, unlike RAR, AP-1 binding activity is not correlated with ATRA sensitivity in HER2-overexpressing breast cancer cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Female
  • GRB2 Adaptor Protein
  • Genes, jun / physiology
  • Humans
  • Oligonucleotides, Antisense / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Retinoic Acid / metabolism
  • Transcription Factor AP-1 / genetics*
  • Transcription Factor AP-1 / metabolism
  • Tretinoin / therapeutic use
  • Tumor Cells, Cultured
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Receptors, Retinoic Acid
  • Transcription Factor AP-1
  • Tretinoin
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt