A Mechanism for Androgen Receptor-mediated Prostate Cancer Recurrence after Androgen Deprivation Therapy

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A Mechanism for Androgen Receptor-mediated Prostate Cancer Recurrence after Androgen Deprivation Therapy¹

Christopher W. Gregory, Bin He, Raymond T. Johnson, O. Harris Ford, James L. Mohler, Frank S. French and Elizabeth M. Wilson²

Laboratories for Reproductive Biology [C. W. G., B. H., R. T. J., F. S. F., E. M. W.], Department of Pediatrics, [C. W. G., B. H., R. T. J., F. S. F., E. M. W.], Lineberger Comprehensive Cancer Center [C. W. G., O. H. F., J. L. M., F. S. F., E. M. W.], and Departments of Biochemistry and Biophysics [B. H., E. M. W.] and Surgery [J. L. M.], Division of Urology [J. L. M.], University of North Carolina, Chapel Hill, North Carolina 27599

The development and growth of prostate cancer depends on theandrogen receptor and its high-affinity binding of dihydrotestosterone,which derives from testosterone. Most prostate tumors regressafter therapy to prevent testosterone production by the testes,but the tumors eventually recur and cause death. A criticalquestion is whether the androgen receptor mediates recurrenttumor growth after androgen deprivation therapy. Here we reportthat a majority of recurrent prostate cancers express high levelsof the androgen receptor and two nuclear receptor coactivators,transcriptional intermediary factor 2 and steroid receptor coactivator1. Overexpression of these coactivators increases androgen receptortransactivation at physiological concentrations of adrenal androgen.Furthermore, we provide a molecular basis for this activationand suggest a general mechanism for recurrent prostate cancergrowth.

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Clin. Cancer Res., February 1, 2004; 10(3): 1032 - 1040.
[Abstract] [Full Text] [PDF]

J. L. Mohler, C. W. Gregory, O. H. Ford III, D. Kim, C. M. Weaver, P. Petrusz, E. M. Wilson, and F. S. French
The Androgen Axis in Recurrent Prostate Cancer
Clin. Cancer Res., January 15, 2004; 10(2): 440 - 448.
[Abstract] [Full Text] [PDF]

J. Holzbeierlein, P. Lal, E. LaTulippe, A. Smith, J. Satagopan, L. Zhang, C. Ryan, S. Smith, H. Scher, P. Scardino, et al.
Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance
Am. J. Pathol., January 1, 2004; 164(1): 217 - 227.
[Abstract] [Full Text] [PDF]

S.-Z. Yang and S. A. Abdulkadir
Early Growth Response Gene 1 Modulates Androgen Receptor Signaling in Prostate Carcinoma Cells
J. Biol. Chem., October 10, 2003; 278(41): 39906 - 39911.
[Abstract] [Full Text] [PDF]

K. Nishimura, H.-J. Ting, Y. Harada, T. Tokizane, N. Nonomura, H.-Y. Kang, H.-C. Chang, S. Yeh, H. Miyamoto, M. Shin, et al.
Modulation of Androgen Receptor Transactivation by Gelsolin: A Newly Identified Androgen Receptor Coregulator
Cancer Res., August 15, 2003; 63(16): 4888 - 4894.
[Abstract] [Full Text] [PDF]

T. W. Marshall, K. A. Link, C. E. Petre-Draviam, and K. E. Knudsen
Differential Requirement of SWI/SNF for Androgen Receptor Activity
J. Biol. Chem., August 15, 2003; 278(33): 30605 - 30613.
[Abstract] [Full Text] [PDF]

I. U. Agoulnik, W. C. Krause, W. E. Bingman III, H. T. Rahman, M. Amrikachi, G. E. Ayala, and N. L. Weigel
Repressors of Androgen and Progesterone Receptor Action
J. Biol. Chem., August 15, 2003; 278(33): 31136 - 31148.
[Abstract] [Full Text] [PDF]

Y. Pan, J.-S. Zhang, M. H. Gazi, and C. Y. F. Young
The Cyclooxygenase 2-specific Nonsteroidal Anti-inflammatory Drugs Celecoxib and Nimesulide Inhibit Androgen Receptor Activity via Induction of c-Jun in Prostate Cancer Cells
Cancer Epidemiol. Biomarkers Prev., August 1, 2003; 12(8): 769 - 774.
[Abstract] [Full Text] [PDF]

W.A. Schulz, M. Burchardt, and M.V. Cronauer
Molecular biology of prostate cancer
Mol. Hum. Reprod., August 1, 2003; 9(8): 437 - 448.
[Abstract] [Full Text] [PDF]

L. Zhang, M. Johnson, K. H. Le, M. Sato, R. Ilagan, M. Iyer, S. S. Gambhir, L. Wu, and M. Carey
Interrogating Androgen Receptor Function in Recurrent Prostate Cancer
Cancer Res., August 1, 2003; 63(15): 4552 - 4560.
[Abstract] [Full Text] [PDF]

P. Y. Liu, A. K. Death, and D. J. Handelsman
Androgens and Cardiovascular Disease
Endocr. Rev., June 1, 2003; 24(3): 313 - 340.
[Abstract] [Full Text] [PDF]

R. E. Bakin, D. Gioeli, E. A. Bissonette, and M. J. Weber
Attenuation of Ras Signaling Restores Androgen Sensitivity to Hormone-refractory C4-2 Prostate Cancer Cells
Cancer Res., April 15, 2003; 63(8): 1975 - 1980.
[Abstract] [Full Text] [PDF]

R. E. Bakin, D. Gioeli, R. A. Sikes, E. A. Bissonette, and M. J. Weber
Constitutive Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway Promotes Androgen Hypersensitivity in LNCaP Prostate Cancer Cells
Cancer Res., April 15, 2003; 63(8): 1981 - 1989.
[Abstract] [Full Text] [PDF]

B. He and E. M. Wilson
Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs
Mol. Cell. Biol., March 15, 2003; 23(6): 2135 - 2150.
[Abstract] [Full Text] [PDF]

M. C. Louie, H. Q. Yang, A.-H. Ma, W. Xu, J. X. Zou, H.-J. Kung, and H.-W. Chen
Androgen-induced recruitment of RNA polymerase II to a nuclear receptor-p160 coactivator complex
PNAS, March 4, 2003; 100(5): 2226 - 2230.
[Abstract] [Full Text] [PDF]

L.-N. Song, R. Herrell, S. Byers, S. Shah, E. M. Wilson, and E. P. Gelmann
{beta}-Catenin Binds to the Activation Function 2 Region of the Androgen Receptor and Modulates the Effects of the N-Terminal Domain and TIF2 on Ligand-Dependent Transcription
Mol. Cell. Biol., March 1, 2003; 23(5): 1674 - 1687.
[Abstract] [Full Text] [PDF]

D. J. Lamb, E. Puxeddu, N. Malik, D. L. Stenoien, R. Nigam, G. Y. Saleh, M. Mancini, N. L. Weigel, and M. Marcelli
Molecular Analysis of the Androgen Receptor in Ten Prostate Cancer Specimens Obtained Before and After Androgen Ablation
J Androl, March 1, 2003; 24(2): 215 - 225.
[Abstract] [Full Text] [PDF]

S. P. Balk, Y.-J. Ko, and G. J. Bubley
Biology of Prostate-Specific Antigen
J. Clin. Oncol., January 15, 2003; 21(2): 383 - 391.
[Abstract] [Full Text] [PDF]

B. Comuzzi, L. Lambrinidis, H. Rogatsch, S. Godoy-Tundidor, N. Knezevic, I. Krhen, Z. Marekovic, G. Bartsch, H. Klocker, A. Hobisch, et al.
The Transcriptional Co-Activator cAMP Response Element-Binding Protein-Binding Protein Is Expressed in Prostate Cancer and Enhances Androgen- and Anti-Androgen-Induced Androgen Receptor Function
Am. J. Pathol., January 1, 2003; 162(1): 233 - 241.
[Abstract] [Full Text] [PDF]

T. Ueda, N. R. Mawji, N. Bruchovsky, and M. D. Sadar
Ligand-independent Activation of the Androgen Receptor by Interleukin-6 and the Role of Steroid Receptor Coactivator-1 in Prostate Cancer Cells
J. Biol. Chem., October 4, 2002; 277(41): 38087 - 38094.
[Abstract] [Full Text] [PDF]

D. Masiello, S. Cheng, G. J. Bubley, M. L. Lu, and S. P. Balk
Bicalutamide Functions as an Androgen Receptor Antagonist by Assembly of a Transcriptionally Inactive Receptor
J. Biol. Chem., July 12, 2002; 277(29): 26321 - 26326.
[Abstract] [Full Text] [PDF]

B. He, L. W. Lee, J. T. Minges, and E. M. Wilson
Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction
J. Biol. Chem., July 5, 2002; 277(28): 25631 - 25639.
[Abstract] [Full Text] [PDF]

E. P. Gelmann
Molecular Biology of the Androgen Receptor
J. Clin. Oncol., July 1, 2002; 20(13): 3001 - 3015.
[Abstract] [Full Text] [PDF]

C. W. Gregory, E. M. Wilson, K. B. C. Apparao, R. A. Lininger, W. R. Meyer, A. Kowalik, M. A. Fritz, and B. A. Lessey
Steroid Receptor Coactivator Expression throughout the Menstrual Cycle in Normal and Abnormal Endometrium
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2960 - 2966.
[Abstract] [Full Text] [PDF]

C. A. Heinlein and C. Chang
Androgen Receptor (AR) Coregulators: An Overview
Endocr. Rev., April 1, 2002; 23(2): 175 - 200.
[Abstract] [Full Text] [PDF]

B. He, J. T. Minges, L. W. Lee, and E. M. Wilson
The FXXLF Motif Mediates Androgen Receptor-specific Interactions with Coregulators
J. Biol. Chem., March 15, 2002; 277(12): 10226 - 10235.
[Abstract] [Full Text] [PDF]