β-catenin activation drives thymoma initiation and progression in mice

Abstract

Thymoma is the most commonly identified cancer in the anterior mediastinum. To date, the causal mechanism that drives thymoma progression is not clear. Here, we generated K5-∆N64Ctnnb1/ERT2 transgenic mice, which express an N-terminal deletion mutant of β-catenin fused to a mutated ligand-binding domain of estrogen receptor (ERT2) under the control of the bovine cytokeratin 5 (K5) promoter. The transgenic mouse lines named Tg1 and Tg4 were characterized. Forced expression of ∆N64Ctnnb1/ERT2 in the Tg1 and Tg4 mice developed small thymoma lesions in response to tamoxifen treatment. In the absence of tamoxifen, the Tg1 mice exhibited leaky activation of β-catenin, which activated the TOP-Gal transgene and Wnt/β-catenin-targeted genes. As the Tg1 mice aged in the absence of tamoxifen, manifest thymomas were found at 10-12 months. Interestingly, we detected loss of AIRE and increase of p63 in the thymomas of Tg1 mice, similar to that observed in human thymomas. Moreover, the β5t protease subunit, which was reported as a differential marker for human type B3 thymoma, was expressed in the Tg1 thymomas. Thus, the Tg1 mice generated in this study accurately mimic the characteristics of human thymomas and may serve as a model for understanding thymoma pathogenesis.