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Activation of the PI3K/AKT Pathway Induces Urothelial Carcinoma of the Renal Pelvis: Identification in Human Tumors and Confirmation in Animal Models

Laboratories of ¹ Cancer Genetics, ² Computational Biology, ³ Molecular Epidemiology, ⁴ Analytical, Cellular, and Molecular Microscopy, and ⁵ Cell Signaling and Carcinogenesis and ⁶ Division of Quantitative Sciences, Van Andel Research Institute; ⁷ Department of Urology, Spectrum Health Hospital, Grand Rapids, Michigan; ⁸ State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China; ⁹ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; ¹⁰ Service d'Anatomie Pathologique, Hôpital d'Instruction des Armées Val de Grâce; ¹¹ Service d'Anatomie Pathologique, CHU Pitié Salpétrière; ¹² Service d'Anatomie Pathologique, CHU Ternon; ¹³ Service d'Anatomie Pathologique, Hopital Saint Joseph; ¹⁴ Service d'Anatomie Pathologique, CHU Cochin, Paris, France; ¹⁵ Service d'Anatomie Pathologique, Hopital Foch, Suresnes, France; and ¹⁶ Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio

Requests for reprints: Chao-Nan Qian, Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503. Phone: 616-990-5070; E-mail: chaonan.qian{at}vai.org or Bin Tean Teh, Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503. Phone: 616-234-5296; Fax: 616-234-5297; E-mail: bin.teh{at}vai.org.

Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents. [Cancer Res 2009;69(21):8256–64]

Key Words: Phosphatidylinositol-3-kinase • PTEN • urothelial carcinoma • renal pelvis • animal model