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Down-regulation of p57^Kip2 Induces Prostate Cancer in the Mouse

¹ Vanderbilt Prostate Cancer Center and Department of Urologic Surgery and ² Department of Pathology, Vanderbilt University Medical Center, Nashville, Tenessee; ³ Department of Urology, Konkuk University Hospital, Seoul, Korea; ⁴ Department of Pathology and Laboratory Medicine, University of Utah, Huntsman Cancer Hospital, Salt Lake City, Utah; ⁵ Department of Urology and Pharmacology, New York University School of Medicine, New York, New York; and ⁶ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas

Requests for reprints: Robert J. Matusik, Department of Urologic Surgery, A-1302 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2765. Phone: 615-322-2142; Fax: 615-322-8990; E-mail: robert.matusik{at}vanderbilt.edu.

Key Words: cancer • P57kip2 • prostate

p57^Kip2 has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57^Kip2 in tumorigenesis and cancer progression. Here, we show that the expression of p57^Kip2 is significantly decreased in human prostate cancer, and the overexpression of p57^Kip2 in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57^Kip2 in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57^Kip2 knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57^Kip2 is an important gene in prostate cancer tumorigenesis, and the p57^Kip2 pathway may be a potential target for prostate cancer prevention and therapy. [Cancer Res 2008;68(10):3601–8]

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