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

Edgar Mendoza-Gamboa1, Doris R Siwak, Ana M Tari

  • 1Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Oncology Reports
|September 18, 2004
PubMed

Insights

The HER2/Grb2/Akt pathway causes resistance to all-trans retinoic acid (ATRA) in breast cancer by affecting DNA binding. AP-1 activity was investigated for its role in this resistance, revealing it is not correlated with ATRA sensitivity in HER2-overexpressing cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The HER2/Grb2/Akt pathway is implicated in promoting resistance to all-trans retinoic acid (ATRA) in breast cancer.
  • This resistance is mediated by the suppression of retinoic acid receptor (RAR) DNA binding activity.
  • AP-1 activation has also been linked to ATRA resistance.

Purpose of the Study:

  • To investigate the correlation between AP-1 binding activity and ATRA resistance in HER2-overexpressing breast cancer cells.
  • To understand the role of the HER2/Grb2/Akt pathway in modulating AP-1 activity in different HER2-expressing contexts.

Main Methods:

  • Utilized HER2-transfected and naturally HER2-overexpressing breast cancer cell lines.
  • Inhibited the HER2/Grb2/Akt pathway.
  • Assessed AP-1 binding activity.
  • Evaluated sensitivity to all-trans retinoic acid (ATRA).

Main Results:

  • Inhibition of HER2/Grb2/Akt decreased AP-1 binding activity in HER2-transfected cells.
  • Conversely, HER2/Grb2/Akt inhibition increased AP-1 activity in naturally HER2-overexpressing cells.
  • Despite differential effects on AP-1, HER2/Grb2/Akt inhibition sensitized both cell types to ATRA.

Conclusions:

  • AP-1 binding activity is not correlated with ATRA sensitivity in HER2-overexpressing breast cancer cells.
  • The mechanism of ATRA resistance in HER2-overexpressing cells is distinct from the direct impact of AP-1 binding activity on RAR function.

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