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J. Biol. Chem., Vol. 281, Issue 38, 27882-27893, September 22, 2006

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Ligand-independent Androgen Receptor Activity Is Activation Function-2-independent and Resistant to Antiandrogens in Androgen Refractory Prostate Cancer Cells^*

From the Departments of Urology and Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Androgen ablation inhibits androgen receptor (AR) activity and is as an effective treatment for advanced prostate cancer (PCa). Invariably, PCa relapses in a form resistant to further hormonal manipulations. Although this stage of the disease is androgen-refractory, or androgen depletion-independent (ADI), most tumors remain AR-dependent through aberrant mechanisms of AR activation. We employed the LNCaP/C4-2 model of PCa progression to study AR activity in androgen-dependent and ADI PCa cells. In this report, we show that the AR is transcriptionally inactive in androgen-dependent LNCaP cells in the absence of androgens. However, in ADI C4-2 cells, the AR displays a high level of constitutive, androgen-independent transcriptional activity. To study the mechanisms of ligand-dependent and ligand-independent AR activation in these AR-expressing cells, we generated a reporter system based on swapping the DNA binding domain of the AR with the DNA binding domain of the yeast Gal4 transcription factor. In androgen-dependent PCa cells, the well characterized C-terminal AR activation function-2 (AF-2) domain was critical for strong, ligand-dependent activity. Conversely, in ADI PCa cells, constitutive, ligand-independent AR activity was AF-2-independent but instead dependent on N-terminal AR domains. Importantly, the ligand- and AF-2-independent mode of AR activation observed in ADI PCa cells was completely resistant to the antiandrogen, bicalutamide. Our data thus demonstrate that the AR can inappropriately activate transcription in ADI PCa cells via mechanisms that are resistant to castration and AR antagonism, the two modes of androgen ablation used to treat advanced PCa.

Received for publication, May 24, 2006 , and in revised form, July 17, 2006.

^* This work was supported in part by National Institutes of Health Grants D65236 [GenBank] , DK60920, and CA91956 and the T. J. Martell Foundation (to D. J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A research fellow of the Terry Fox Foundation through a grant from the National Cancer Institute of Canada.

² To whom correspondence should be addressed: Dept. of Urologic Research, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-8139; Fax: 507-284-2384; E-mail: tindall.donald{at}mayo.edu.

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