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Model Organisms

Bub1 Up-Regulation and Hyperphosphorylation Promote Malignant Transformation in SV40 Tag–Induced Transgenic Mouse Models

Departments of ¹ Surgery, ² Pathology, and ³ Oncology, University of Western Ontario, London, Ontario, Canada; ⁴ Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas; ⁵ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁶ School of Biological Sciences, University of Manchester, Manchester, United Kingdom

Requests for reprints: Jim W. Xuan, Urology Research Laboratory, London Health Sciences Centre, 375 South Street, London, Ontario, Canada N6A 4G5. Phone: 519-667-6682; Fax: 519-432-7367. E-mail: jim.xuan{at}lhsc.on.ca

Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by 10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA–mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America. (Mol Cancer Res 2006;4(12):957–69)