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Article
Nature Medicine  10, 33 - 39 (2004)
Published online: 21 December 2003; | doi:10.1038/nm972

Molecular determinants of resistance to antiandrogen therapy

Charlie D Chen1, 5, 8, Derek S Welsbie3, 5, 8, Chris Tran1, 4, Sung Hee Baek4, 6, Randy Chen1, Robert Vessella7, Michael G Rosenfeld4, 6 & Charles L Sawyers1, 2, 3, 4, 5

1  Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.

2  Departments of Molecular Pharmacology and Urology, University of California at Los Angeles, Los Angeles, California 90095, USA.

3  Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.

4  Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.

5  David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California 90095, USA.

6  University of California at San Diego School of Medicine, San Diego, California 92093, USA.

7  Department of Urology, University of Washington, Seattle, Washington 98195, USA.

8  These authors contributed equally to this work.

Correspondence should be addressed to Charles L Sawyers csawyers@mednet.ucla.edu
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.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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