Molecular determinants of resistance to antiandrogen therapy
- PMID: 14702632
- DOI: 10.1038/nm972
Molecular determinants of resistance to antiandrogen therapy
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.
Comment in
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Androgen receptor outwits prostate cancer drugs.Nat Med. 2004 Jan;10(1):26-7. doi: 10.1038/nm0104-26. Nat Med. 2004. PMID: 14702629 No abstract available.
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