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Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen

¹ Department of Genetics, Cell Biology, and Development and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; ² Division of Pharmaceutical Sciences, School of Pharmacy and University of Wisconsin Carbone Comprehensive Cancer Center, and ³ Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin; and ⁴ Mouse Cancer Genetics Program, National Cancer Institute in Frederick, Frederick, Maryland

Requests for reprints: Paul C. Marker, Division of Pharmaceutical Sciences, School of Pharmacy and University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705. Phone: 608-890-2150; Fax: 608-262-5345; E-mail: marker{at}wisc.edu.

Key Words: mouse genetics • prostate cancer • Sleeping Beauty transposon

Retroviral and transposon-based mutagenesis screens in mice have been useful for identifying candidate cancer genes for some tumor types. However, many of the organs that exhibit the highest cancer rates in humans, including the prostate, have not previously been amenable to these approaches. This study shows for the first time that the Sleeping Beauty transposon system can be used to identify candidate prostate cancer genes in mice. Somatic mobilization of a mutagenic transposon resulted in focal epithelial proliferation and hyperplasia in the prostate. Efficient methods were established to identify transposon insertion sites in these lesions, and analysis of transposon insertions identified candidate prostate cancer genes at common insertion sites, including Pde4d. PDE4D was also overexpressed in human prostate cancer patient samples and cell lines, and changes in PDE4D mRNA isoform expression were observed in human prostate cancers. Furthermore, knockdown of PDE4D reduced the growth and migration of prostate cancer cells in vitro, and knockdown of PDE4D reduced the growth and proliferation rate of prostate cancer xenografts in vivo. These data indicate that PDE4D functions as a proliferation promoting factor in prostate cancer, and the Sleeping Beauty transposon system is a useful tool for identifying candidate prostate cancer genes. [Cancer Res 2009;69(10):4388–97]

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