Molecular determinants of resistance to antiandrogen therapy. Academic Article uri icon

Overview

abstract

  • Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

publication date

  • December 21, 2003

Research

keywords

  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • Drug Resistance, Neoplasm
  • Prostatic Neoplasms

Identity

Scopus Document Identifier

  • 1842612441

PubMed ID

  • 14702632

Additional Document Info

volume

  • 10

issue

  • 1