This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, L. Articles by Carey, M. Search for Related Content PubMed PubMed Citation Articles by Zhang, L. Articles by Carey, M.

Interrogating Androgen Receptor Function in Recurrent Prostate Cancer^{1 ,2}

Departments of Biological Chemistry [L. Z., K. H. L., R. I., M. C.] and Urology [M. J., M. S., L. W.], Crump Institute of Molecular Imaging [S. S. G., L. W., M. C.], and Department of Molecular and Medical Pharmacology [M. I., S. S. G.], University of California, Los Angeles, School of Medicine, Los Angeles, California 90095

The early androgen-dependent (AD) phase of prostate cancer is dependent on the androgen receptor (AR). However, it is unclear whether AR is fully functional in recurrent prostate cancer after androgen withdrawal. To address this issue we interrogated AR signaling in AD and recurrent prostate cancer xenografts using molecular imaging, chromatin immunoprecipitation, and immunohistochemistry. In the imaging experiments, an adenovirus bearing a two-step transcriptional activation cassette, which amplifies AR-dependent firefly luciferase reporter gene activity, was injected into tumors implanted into severe combined immunodeficiency mice. A charge-coupled device optical imaging system detected the initial loss and then resumption of AR transcriptional activity in D-luciferin-injected mice as tumors transitioned from AD to recurrent growth. The results of chromatin immunoprecipitation and immunohistochemical localization experiments correlated with the Ad two-step transcriptional activation imaging signal. AR localized to the nucleus and bound to the endogenous prostate-specific antigen enhancer in AD tumors but exited the nucleus and dissociated from the enhancer upon castration. However, AR reentered the nucleus and rebound the prostate-specific antigen enhancer as the cancer transitioned into the recurrent phase. Surprisingly, RNA polymerase II and the general factor TFIIB remained bound to the gene throughout the transition. Our data support the concept that AR is fully functional in recurrent cancer and suggest a model by which a poised but largely inactive transcription complex facilitates reactivation by AR at castrate levels of ligand.

This article has been cited by other articles:

				L. A. Ponguta, C. W. Gregory, F. S. French, and E. M. Wilson Site-specific Androgen Receptor Serine Phosphorylation Linked to Epidermal Growth Factor-dependent Growth of Castration-recurrent Prostate Cancer J. Biol. Chem., July 25, 2008; 283(30): 20989 - 21001. [Abstract] [Full Text] [PDF]

				L. C. Shank, J. B. Kelley, D. Gioeli, C.-S. Yang, A. Spencer, L. A. Allison, and B. M. Paschal Activation of the DNA-dependent Protein Kinase Stimulates Nuclear Export of the Androgen Receptor in Vitro J. Biol. Chem., April 18, 2008; 283(16): 10568 - 10580. [Abstract] [Full Text] [PDF]

				T. Bawa-Khalfe, J. Cheng, Z. Wang, and E. T. H. Yeh Induction of the SUMO-specific Protease 1 Transcription by the Androgen Receptor in Prostate Cancer Cells J. Biol. Chem., December 28, 2007; 282(52): 37341 - 37349. [Abstract] [Full Text] [PDF]

				S. M. Dehm and D. J. Tindall Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer Mol. Endocrinol., December 1, 2007; 21(12): 2855 - 2863. [Abstract] [Full Text] [PDF]

				C. T. Kesler, D. Gioeli, M. R. Conaway, M. J. Weber, and B. M. Paschal Subcellular Localization Modulates Activation Function 1 Domain Phosphorylation in the Androgen Receptor Mol. Endocrinol., September 1, 2007; 21(9): 2071 - 2084. [Abstract] [Full Text] [PDF]

				C.-S. Yang, H.-W. Xin, J. B. Kelley, A. Spencer, D. L. Brautigan, and B. M. Paschal Ligand Binding to the Androgen Receptor Induces Conformational Changes That Regulate Phosphatase Interactions Mol. Cell. Biol., May 1, 2007; 27(9): 3390 - 3404. [Abstract] [Full Text] [PDF]

				R. Ilagan, J. Pottratz, K. Le, L. Zhang, S. G. Wong, R. Ayala, M. Iyer, L. Wu, S. S. Gambhir, and M. Carey Imaging Mitogen-Activated Protein Kinase Function in Xenograft Models of Prostate Cancer. Cancer Res., November 15, 2006; 66(22): 10778 - 10785. [Abstract] [Full Text] [PDF]

				S. K. Lyons, E. Lim, A. O. Clermont, J. Dusich, L. Zhu, K. D. Campbell, R. J. Coffee, D. S. Grass, J. Hunter, T. Purchio, et al. Noninvasive Bioluminescence Imaging of Normal and Spontaneously Transformed Prostate Tissue in Mice. Cancer Res., May 1, 2006; 66(9): 4701 - 4707. [Abstract] [Full Text] [PDF]

				D. Gioeli, B. E. Black, V. Gordon, A. Spencer, C. T. Kesler, S. T. Eblen, B. M. Paschal, and M. J. Weber Stress Kinase Signaling Regulates Androgen Receptor Phosphorylation, Transcription, and Localization Mol. Endocrinol., March 1, 2006; 20(3): 503 - 515. [Abstract] [Full Text] [PDF]

				R. Ilagan, L. J. Zhang, J. Pottratz, K. Le, S. Salas, M. Iyer, L. Wu, S. S. Gambhir, and M. Carey Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model Mol. Cancer Ther., November 1, 2005; 4(11): 1662 - 1669. [Abstract] [Full Text] [PDF]

				C-L Hsieh, Z Xie, Z-Y Liu, J E Green, W D Martin, M W Datta, F Yeung, D Pan, and L W K Chung A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals J. Mol. Endocrinol., October 1, 2005; 35(2): 293 - 304. [Abstract] [Full Text] [PDF]

				I. U. Agoulnik, A. Vaid, W. E. Bingman III, H. Erdeme, A. Frolov, C. L. Smith, G. Ayala, M. M. Ittmann, and N. L. Weigel Role of SRC-1 in the Promotion of Prostate Cancer Cell Growth and Tumor Progression Cancer Res., September 1, 2005; 65(17): 7959 - 7967. [Abstract] [Full Text] [PDF]

				M. Sato, M. Johnson, L. Zhang, S. S. Gambhir, M. Carey, and L. Wu Functionality of Androgen Receptor-Based Gene Expression Imaging in Hormone Refractory Prostate Cancer Clin. Cancer Res., May 15, 2005; 11(10): 3743 - 3749. [Abstract] [Full Text] [PDF]

				X. Liao, S. Tang, J. B. Thrasher, T. L. Griebling, and B. Li Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer Mol. Cancer Ther., April 1, 2005; 4(4): 505 - 515. [Abstract] [Full Text] [PDF]

				Y. B. Wetherill, N. L. Fisher, A. Staubach, M. Danielsen, R. W. de Vere White, and K. E. Knudsen Xenoestrogen Action in Prostate Cancer: Pleiotropic Effects Dependent on Androgen Receptor Status Cancer Res., January 1, 2005; 65(1): 54 - 65. [Abstract] [Full Text] [PDF]