This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Shen, H. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Shen, H. Articles by Knudsen, K. E.

The SWI/SNF ATPase Brm Is a Gatekeeper of Proliferative Control in Prostate Cancer

¹ Department of Cell and Cancer Biology, University of Cincinnati, ² Cincinnati Children's Hospital, Cincinnati, Ohio; ³ Department of Pathology, University of Utah, Salt Lake City, Utah; ⁴ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁵ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina; ⁶ Department of Developmental Biology, Institut Pasteur, Paris, France; and Departments of ⁷ Cancer Biology and ⁸ Urology, Thomas Jefferson University/Kimmel Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Karen E. Knudsen, Thomas Jefferson University/Kimmel Cancer Center, Bluemle Building, Room 1008, Philadelphia, PA 19107. Phone: 215-503-8574; Fax: 215-503-8574; E-mail: karen.knudsen{at}kimmelcancercenter.org.

Key Words: androgen • chromatin remodeling • E2F1 • prostatic adenocarcinoma • tumor suppressor

Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm–/– epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen–induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer. [Cancer Res 2008;68(24):10154–62]

This article has been cited by other articles:

				B. Weissman and K. E. Knudsen Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Cancer Res., November 1, 2009; 69(21): 8223 - 8230. [Abstract] [Full Text] [PDF]

				C. E.S. Comstock, M. A. Augello, R. P. Benito, J. Karch, T. H. Tran, F. E. Utama, E. A. Tindall, Y. Wang, C. J. Burd, E. M. Groh, et al. Cyclin D1 Splice Variants: Polymorphism, Risk, and Isoform-Specific Regulation in Prostate Cancer Clin. Cancer Res., September 1, 2009; 15(17): 5338 - 5349. [Abstract] [Full Text] [PDF]