Thymidylate synthase (TS) is a key enzyme for DNA biosynthesis during cellular proliferation. Studies from our laboratory have demonstrated oncogenic activity of TS in mammalian cells (Cancer Cell, 5 p341, 2004) and in transgenic mice that overexpress human TS (hTS) (Oncogene v26 p4814, 2007). To investigate the in vivo role of TS in pituitary tumorigenesis, we crossed hTS transgenic mice with conditional Men1 knockout mice. We found that overexpression of hTS in fMen1−/− mice significantly decreased the age of onset and increased the incidence of pituitary tumors. fMen1−/−hTS mice developed adenoma and carcinoma as early as 6 and 7 month respectively, while the development of these tumor was not observed in fMen1−/− mice until after 8 month of age. By 8 months of age, 12.1% fMen1−/−hTS mice developed adenoma while no adenoma was observed in fMen1−/− mice. At 10 month of age, progression of pituitary adenoma to carcinoma occurred with higher incidence (51.6%) in fMen1−/−hTS as compared to fMen1−/− mice (18.2%) (p=0.013). Using immunohistochemistry and immunoblotting analysis we confirmed expression of ectopic hTS protein in pituitary tumors of fMen1−/−hTS mice. Our results demonstrated that TS enhances the development and progression of pituitary tumors and suggested that this transgenic model can be use to study the in vivo consequences of elevated hTS on DNA stability, to test how this relates to tumorigenesis, and to improve the use of hTS as a biomarker and therapeutic target. The impact of this work is that it would show that elevated hTS is playing an active role in promoting tumor cell proliferation and is not a simply a passive target for chemotherapy agents to induce cellular toxicity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4191.