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Impact of PKCdelta on estrogen receptor localization and activity in breast cancer cells

Barbara De Servi1, Alexander Hermani, Senad Medunjanin

  • 1Deutsches Krebsforschungszentrum, Hormones and Signal Transduction, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.

Oncogene
|April 13, 2005
PubMed

Insights

Protein Kinase C delta (PKCdelta) activation promotes breast cancer cell proliferation by enhancing estrogen receptor alpha (ERalpha) activity. This involves glycogen synthase kinase-3 (GSK3) in ERalpha nuclear translocation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Estrogen receptor (ER) function is crucial in breast cancer.
  • Protein Kinase C (PKC) signaling pathways influence ER activity.
  • PKCdelta, a novel PKC isoenzyme, is implicated in cell growth and apoptosis.

Purpose of the Study:

  • To investigate the role of PKCdelta in regulating the transcriptional activity of human ERalpha.
  • To elucidate the signaling mechanisms by which PKCdelta affects ERalpha function in breast cancer cells.

Main Methods:

  • Utilized pharmacological activators (TPA, Bryostatin1) and inhibitors (Rottlerin) of PKC.
  • Employed reporter gene assays to measure ER-dependent transcriptional activity.
  • Used transfection of inhibitory domain (RDdelta) to block PKCdelta activity.
  • Investigated protein phosphorylation and cellular localization via Western blotting and microscopy.

Main Results:

  • Active PKCdelta acts as a pro-proliferative factor in estrogen-dependent breast cancer cells.
  • PKCdelta activation by TPA leads to ERalpha activation and nuclear translocation, increasing ER-dependent gene expression.
  • Inhibition of PKCdelta by RDdelta blocked TPA-induced ERalpha activation and translocation.
  • PKCdelta phosphorylates glycogen synthase kinase-3 (GSK3), which is involved in TPA-induced GSK3 nuclear translocation.

Conclusions:

  • PKCdelta plays a significant role in promoting proliferation in ER-positive breast cancer cells.
  • GSK3 is a downstream target of PKCdelta and mediates ERalpha nuclear translocation.
  • This study identifies a novel signaling axis (PKCdelta-GSK3-ERalpha) regulating ER transcriptional activity in breast cancer.

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