HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Academic Article uri icon

Overview

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 date

  • November 1, 2004

Research

keywords

  • Prostatic Neoplasms
  • Pyrimidines
  • Pyrroles
  • Receptor, ErbB-2
  • Receptors, Androgen

Identity

Scopus Document Identifier

  • 7944234374

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2004.09.031

PubMed ID

  • 15542435

Additional Document Info

volume

  • 6

issue

  • 5