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Molecular determinants of resistance to antiandrogen therapy

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 bot... Full description

Journal Title: Nature medicine 2004-01, Vol.10 (1), p.33-39
Main Author: Sawyers, Charles L
Other Authors: Chen, Charlie D , Welsbie, Derek S , Tran, Chris , Baek, Sung Hee , Chen, Randy , Vessella, Robert , Rosenfeld, Michael G
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/14702632
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title: Molecular determinants of resistance to antiandrogen therapy
format: Article
creator:
  • Sawyers, Charles L
  • Chen, Charlie D
  • Welsbie, Derek S
  • Tran, Chris
  • Baek, Sung Hee
  • Chen, Randy
  • Vessella, Robert
  • Rosenfeld, Michael G
subjects:
  • Androgen Antagonists - pharmacology
  • Androgen Antagonists - therapeutic use
  • Antineoplastic Agents, Hormonal - pharmacology
  • Antineoplastic Agents, Hormonal - therapeutic use
  • Base Sequence
  • Disease Progression
  • DNA Primers
  • Drug Resistance, Neoplasm
  • Humans
  • Male
  • Prostatic Neoplasms - drug therapy
  • Prostatic Neoplasms - pathology
  • Prostatic Neoplasms - physiopathology
  • Receptors, Androgen - physiology
ispartof: Nature medicine, 2004-01, Vol.10 (1), p.33-39
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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descriptionUsing 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.
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subjectAndrogen Antagonists - pharmacology ; Androgen Antagonists - therapeutic use ; Antineoplastic Agents, Hormonal - pharmacology ; Antineoplastic Agents, Hormonal - therapeutic use ; Base Sequence ; Disease Progression ; DNA Primers ; Drug Resistance, Neoplasm ; Humans ; Male ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - physiopathology ; Receptors, Androgen - physiology
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abstractUsing 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.
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