HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability

Cancer Cell. 2004 Nov;6(5):517-27. doi: 10.1016/j.ccr.2004.09.031.

Abstract

Given the role of the EGFR/HER2 family of tyrosine kinases in breast cancer, we dissected the molecular basis of EGFR/HER2 kinase signaling in prostate cancer. Using the small molecule dual EGFR/HER2 inhibitor PKI-166, we show that the biologic effects of EGFR/HER-2 pathway inhibition are caused by reduced AR transcriptional activity. Additional genetic and pharmacologic experiments show that this modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR. This HER2/ERBB3 signal stabilizes AR protein levels and optimizes binding of AR to promoter/enhancer regions of androgen-regulated genes. Surprisingly, the downstream signaling pathway responsible for these effects appears to involve kinases other than Akt. These data suggest that the HER2/ERBB3 pathway is a critical target in hormone-refractory prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • DNA, Neoplasm / metabolism
  • ErbB Receptors / physiology
  • Humans
  • Male
  • Prostatic Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • RNA, Small Interfering / pharmacology
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / physiology*
  • Receptors, Androgen / metabolism*
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA, Neoplasm
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Pyrroles
  • RNA, Small Interfering
  • Receptors, Androgen
  • PKI 166
  • ErbB Receptors
  • Receptor, ErbB-2
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt