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Retinoids interfere with the AP1 signalling pathway in human breast cancer cells

Stephane Dedieu1, Philippe Lefebvre

  • 1INSERM U459, Equipe labellisée par la Ligue Nationale contre le Cancer, Faculté de Médecine Henri Warembourg, 1 Place de Verdun, F-59045 Lille Cedex, France. stephane.dedieu@univ-reims.fr

Cellular Signalling
|September 24, 2005
PubMed

Insights

Retinoids, used in cancer prevention, inhibit AP1-responsive genes by blocking MKK6/p38 and MEK/ERK pathways. This action, involving c-jun and c-fos, clarifies how retinoids regulate tumoral cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Retinoids are crucial for cell proliferation and differentiation, showing promise in cancer prevention and treatment.
  • The chemopreventive and chemotherapeutic effects of retinoids are linked to their ability to inhibit AP1-responsive genes.
  • The precise molecular mechanisms underlying retinoid-mediated antiproliferative effects are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which retinoids inhibit AP1-responsive gene expression in human breast cancer cells.
  • To identify specific signaling pathways targeted by retinoids in the context of cancer cell proliferation.
  • To elucidate the role of transcription factors c-jun and c-fos in retinoid-mediated transrepression of AP1 activity.

Main Methods:

  • Treatment of human breast cancer cells with retinoid agonists and antagonists.
  • Analysis of matrix metalloproteinase (MMP) expression, specifically MMP-1 and MMP-3.
  • Investigation of mitogen-activated protein kinase (MAPK) pathways, including MKK6/p38, MEK/ERK, and JNK.
  • Assessment of AP1 activity in cells with overexpressed c-fos and c-jun.

Main Results:

  • Retinoids were shown to inhibit phorbol ester-induced MMP-1 and MMP-3 expression in human breast cancer cells.
  • Retinoid treatment demonstrated both transactivation and transrepression functions.
  • Retinoids repress AP1-responsive gene expression by inhibiting the MKK6/p38 and MEK/ERK signaling pathways, but not the JNK pathway.
  • Overexpression of c-fos and c-jun partially abrogated retinoid-induced inhibition of AP1 activity.

Conclusions:

  • Retinoids antagonize AP1 activity through the inhibition of MKK6/p38 and MEK/ERK signaling pathways.
  • The AP1 transrepressive function of retinoids may involve targeting of c-jun and/or c-fos containing dimers.
  • These findings enhance the understanding of retinoid action in regulating tumoral cell proliferation and offer insights for cancer therapy.

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