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 Davis, J. N. Articles by Day, M. L. Search for Related Content PubMed PubMed Citation Articles by Davis, J. N. Articles by Day, M. L.

Elevated E2F1 Inhibits Transcription of the Androgen Receptor in Metastatic Hormone-Resistant Prostate Cancer

¹ Department of Urology, University of Michigan, Ann Arbor, Michigan; ² Department of Urology, University of Ulm, Ulm, Germany; ³ Department of Pathology, Brigham and Women's Hospital; and ⁴ Harvard University, School of Medicine, Boston, Massachusetts

Requests for reprints: Mark L. Day, Department of Urology, University of Michigan, 6131 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944. Phone: 734-763-9968; Fax: 734-647-9271; E-mail: mday{at}umich.edu.

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone–independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer. (Cancer Res 2006; 66(24): 11897-906)

This article has been cited by other articles:

				J. X. Zou, L. Guo, A. S. Revenko, C. G. Tepper, A. T. Gemo, H.-J. Kung, and H.-W. Chen Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer Cancer Res., April 15, 2009; 69(8): 3339 - 3346. [Abstract] [Full Text] [PDF]

				C. Zheng, Z. Ren, H. Wang, W. Zhang, D. V. Kalvakolanu, Z. Tian, and W. Xiao E2F1 Induces Tumor Cell Survival via Nuclear Factor-{kappa}B-Dependent Induction of EGR1 Transcription in Prostate Cancer Cells Cancer Res., March 15, 2009; 69(6): 2324 - 2331. [Abstract] [Full Text] [PDF]

				T. S. Udayakumar, P. Hachem, M. M. Ahmed, S. Agrawal, and A. Pollack Antisense MDM2 Enhances E2F1-Induced Apoptosis and the Combination Sensitizes Androgen-Dependent and Androgen-Independent Prostate Cancer Cells to Radiation Mol. Cancer Res., November 1, 2008; 6(11): 1742 - 1754. [Abstract] [Full Text] [PDF]

				M. Gaudreault, F. Vigneault, M.-E. Gingras, S. Leclerc, P. Carrier, L. Germain, and S. L. Guerin Transcriptional Regulation of the Human {alpha}6 Integrin Gene by the Transcription Factor NFI during Corneal Wound Healing Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 3758 - 3767. [Abstract] [Full Text] [PDF]

				A. O. Kaseb, K. Chinnakannu, D. Chen, A. Sivanandam, S. Tejwani, M. Menon, Q. P. Dou, and G. P.-V. Reddy Androgen Receptor and E2F-1 Targeted Thymoquinone Therapy for Hormone-Refractory Prostate Cancer Cancer Res., August 15, 2007; 67(16): 7782 - 7788. [Abstract] [Full Text] [PDF]

				A. Sharma, C. E.S. Comstock, E. S. Knudsen, K. H. Cao, J. K. Hess-Wilson, L. M. Morey, J. Barrera, and K. E. Knudsen Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells Cancer Res., July 1, 2007; 67(13): 6192 - 6203. [Abstract] [Full Text] [PDF]