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Androgen receptor expression in prostate cancer cells is suppressed by activation of epidermal growth factor receptor

Changmeng Cai1, David C Portnoy, Hongyun Wang

  • 1Cancer Biology Program/Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Cancer Research
|June 4, 2009
PubMed

Insights

Epidermal growth factor (EGF) receptor (EGFR) and ErbB2 activation rapidly decrease androgen receptor (AR) mRNA levels in prostate cancer cells. This suggests a new strategy to suppress AR expression in castration-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Castration-resistant prostate cancer (CRPC) relapses after androgen deprivation therapy (ADT).
  • CRPC cells maintain high androgen receptor (AR) and androgen-regulated gene expression.
  • ErbB family receptor tyrosine kinases, including epidermal growth factor (EGF) receptor (EGFR) and ErbB2, may enhance AR activity in CRPC.

Purpose of the Study:

  • To investigate the effect of EGFR and ErbB2 activation on AR expression in prostate cancer cells.
  • To determine the mechanism by which EGFR and ErbB2 influence AR levels.
  • To explore potential therapeutic strategies for CRPC targeting AR expression.

Main Methods:

  • Treatment of prostate cancer cell lines (LNCaP, LAPC4, C4-2, CWR22Rv1) with EGF and heregulin-beta1.
  • Analysis of AR and PSA (prostate-specific antigen) protein and mRNA levels.
  • Assessment of AR protein degradation using inhibitors.
  • Investigation of AR mRNA degradation rates using actinomycin D.
  • Culture of cells in androgen-depleted medium.

Main Results:

  • EGF and heregulin-beta1 rapidly decreased AR and PSA expression in LNCaP, LAPC4, and C4-2 cells, but not CWR22Rv1 cells.
  • The decrease in AR was not due to increased protein degradation and was independent of PI3K and MEK signaling pathways.
  • AR mRNA levels were significantly reduced by EGF and heregulin-beta1, indicating increased AR mRNA degradation.
  • In androgen-depleted conditions, EGF and heregulin-beta1 still decreased AR mRNA, though protein levels were stabilized.

Conclusions:

  • EGFR and ErbB2 activation negatively regulate AR mRNA levels in prostate cancer cells.
  • Increased AR mRNA degradation is a key mechanism for this regulation.
  • Targeting EGFR and ErbB2 offers a potential therapeutic approach to suppress AR expression in CRPC.

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