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Differential Expression of Cell Cycle Regulators in Phenotypic Variants of Transgenically Induced Bladder Tumors: Implications for Tumor Behavior

Departments of ¹ Pathology, ² Dermatology, ³ Pharmacology, ⁴ Urology, and ⁵ Microbiology, New York University Cancer Institute; and ⁶ Veterans Affairs Medical Center in Manhattan, New York, New York; and ⁷ Unitat de Recerca, University Hospital Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain

Requests for reprints: Angel Pellicer, Department of Pathology MSB594, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-5342; Fax: 212-263-8211; E-mail: pellia01{at}med.nyu.edu.

Proteins controlling cell growth, differentiation, apoptosis, and oncogenic stress are often deregulated in tumor cells. However, whether such deregulations affect tumor behavior remains poorly understood in many tumor types. We recently showed that the urothelium-specific expression of activated H-ras and SV40 T antigen in transgenic mice produced two distinctive types of tumors strongly resembling the human superficial papillary tumors and carcinoma in situ of the bladder, respectively. Here we assessed the expression of a key set of cell cycle regulators in these mouse tumors and in a new transgenic line expressing a cyclin D1 oncogene in the urothelium. We found that urothelia of the wild-type and cyclin D1 transgenic mice exhibited a profile of cell cycle regulators found in quiescent (G₀) cells, indicating that urothelium overexpressing the cyclin D1 (an 8-fold increase) is reminiscent of normal urothelium and remains slow-cycling. Low-grade superficial papillary tumors induced by activated H-ras had no detectable Rb family proteins (Rb, p107, and p130) and late cell cycle cyclins and kinases (cyclin A, E, and CDK1), but had increased level of p16, p53, and MDM2. These data suggest that the inactivation of the Rb pathway plays an important role in H-ras-induced superficial papillary tumors and that oncogenic H-ras can induce a compensatory activation of alternative tumor suppressor pathways. In contrast, carcinoma in situ of the bladder induced by SV40 T antigen had increased expression of cell cycle regulators mainly active in post-G₁ phases. The fact that phenotypically different bladder tumors exhibit different patterns of cell cycle regulators may explain why these tumors have different propensity to progress to invasive tumors. Our results indicate that the transgenic mouse models can be used not only for studying tumorigenesis but also for evaluating therapeutic strategies that target specific cell cycle regulators.

Key Words: bladder cancer • transgenic mice • H-ras • SV40 large T antigen • cyclin D1

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