Mutation of the Androgen-Receptor Gene in Metastatic Androgen-Independent Prostate Cancer
Mary-Ellen Taplin, M.D., Glenn J. Bubley, M.D., Todd D. Shuster, M.D., Martha E. Frantz, Amy E. Spooner, George K. Ogata, Harold N. Keer, M.D., Ph.D., and Steven P. Balk, M.D.
Background Metastatic prostate cancer is a leading cause ofcancer-related death in men. The rate of response to androgenablation is high, but most patients relapse as a result of theoutgrowth of androgen-independent tumor cells. The androgenreceptor, which binds testosterone and stimulates the transcriptionof androgen-responsive genes, regulates the growth of prostatecells. We analyzed the androgen-receptor genes from samplesof metastatic androgen-independent prostate cancers to determinewhether mutations in the gene have a role in androgen independence.
Methods Complementary DNA was synthesized from metastatic prostatecancers in 10 patients with androgen-independent prostate cancer,and the expression of the androgen-receptor gene was estimatedby amplification with the polymerase chain reaction. Exons Bthrough H of the gene were cloned, and mutations were identifiedby DNA sequencing. The functional effects of the mutations wereassessed in cells transfected with mutant genes.
Results All androgen-independent tumors expressed high levelsof androgen-receptor gene transcripts, relative to the levelsexpressed by an androgen-independent prostate-cancer cell line(LnCap). Point mutations in the androgen-receptor gene wereidentified in metastatic cells from 5 of the 10 patients examined.One mutation was in the same codon as the mutation found previouslyin the androgen-independent prostate-cancer cell line. The mutationswere not detected in the primary tumors from two of the patients.Functional studies of two of the mutant androgen receptors demonstratedthat they could be activated by progesterone and estrogen.
Conclusions Most metastatic androgen-independent prostate cancersexpress high levels of androgen-receptor gene transcripts. Mutationsin androgen-receptor genes are not uncommon and may providea selective growth advantage after androgen ablation.
Source Information
From the Oncology Division, Department of Medicine, University of Massachusetts Medical Center, Worcester (M.-E.T.), and the Hematology–Oncology Division, Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston (G.J.B., T.D.S., M.E.F., A.E.S., G.K.O., H.N.K., S.P.B.).
Address reprint requests to Dr. Balk at the Hematology–Oncology Division, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215.
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Sasaki, M., Tanaka, Y., Perinchery, G., Dharia, A., Kotcherguina, I., Fujimoto, S. i., Dahiya, R.
(2002). Methylation and Inactivation of Estrogen, Progesterone, and Androgen Receptors in Prostate Cancer. JNCI J Natl Cancer Inst
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Shi, X.-B., Ma, A.-H., Xia, L., Kung, H.-J., de Vere White, R. W.
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Miyamoto, H., Rahman, M., Takatera, H., Kang, H.-Y., Yeh, S., Chang, H.-C., Nishimura, K., Fujimoto, N., Chang, C.
(2002). A Dominant-negative Mutant of Androgen Receptor Coregulator ARA54 Inhibits Androgen Receptor-mediated Prostate Cancer Growth. J. Biol. Chem.
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Lee, S. R., Ramos, S. M., Ko, A., Masiello, D., Swanson, K. D., Lu, M. L., Balk, S. P.
(2002). AR and ER Interaction with a p21-Activated Kinase (PAK6). Mol. Endocrinol.
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Chang, C.-Y., Walther, P. J., McDonnell, D. P.
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61: 8712-8717
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Grossmann, M. E., Huang, H., Tindall, D. J.
(2001). Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer. JNCI J Natl Cancer Inst
93: 1687-1697
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Stanbrough, M., Leav, I., Kwan, P. W. L., Bubley, G. J., Balk, S. P.
(2001). Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc. Natl. Acad. Sci. USA
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Taplin, M. E., Ho, S.-M.
(2001). The Endocrinology of Prostate Cancer. J. Clin. Endocrinol. Metab.
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Matsubara, S., Wada, Y., Gardner, T. A., Egawa, M., Park, M.-S., Hsieh, C.-L., Zhau, H. E., Kao, C., Kamidono, S., Gillenwater, J. Y., Chung, L. W. K.
(2001). A Conditional Replication-competent Adenoviral Vector, Ad-OC-E1a, to Cotarget Prostate Cancer and Bone Stroma in an Experimental Model of Androgen-independent Prostate Cancer Bone Metastasis. Cancer Res.
61: 6012-6019
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Reutens, A. T., Fu, M., Wang, C., Albanese, C., McPhaul, M. J., Sun, Z., Balk, S. P., Jänne, O. A., Palvimo, J. J., Pestell, R. G.
(2001). Cyclin D1 Binds the Androgen Receptor and Regulates Hormone-Dependent Signaling in a p300/CBP-Associated Factor (P/CAF)-Dependent Manner. Mol. Endocrinol.
15: 797-811
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Linja, M. J., Savinainen, K. J., Saramäki, O. R., Tammela, T. L. J., Vessella, R. L., Visakorpi, T.
(2001). Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer. Cancer Res.
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Buchanan, G., Greenberg, N. M., Scher, H. I., Harris, J. M., Marshall, V. R., Tilley, W. D.
(2001). Collocation of Androgen Receptor Gene Mutations in Prostate Cancer. Clin. Cancer Res.
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Sack, J. S., Kish, K. F., Wang, C., Attar, R. M., Kiefer, S. E., An, Y., Wu, G. Y., Scheffler, J. E., Salvati, M. E., Krystek, S. R. Jr., Weinmann, R., Einspahr, H. M.
(2001). Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc. Natl. Acad. Sci. USA
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Xing, N., Chen, Y., Mitchell, S. H., Young, C. Y.F.
(2001). Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis
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Fossa, S. D., Slee, P. H.Th., Brausi, M., Horenblas, S., Hall, R. R., Hetherington, J. W., Aaronson, N., de Prijck, L., Collette, L.
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Buchanan, G., Yang, M., Harris, J. M., Nahm, H. S., Han, G., Moore, N., Bentel, J. M., Matusik, R. J., Horsfall, D. J., Marshall, V. R., Greenberg, N. M., Tilley, W. D.
(2001). Mutations at the Boundary of the Hinge and Ligand Binding Domain of the Androgen Receptor Confer Increased Transactivation Function. Mol. Endocrinol.
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