Abstract B24: ATDC (Trim29) drives invasive bladder cancer formation

Bladder cancer is a common and deadly malignancy, but incomplete understanding of the molecular events driving tumor development and metastasis has limited development of effective treatments. Ataxia-Telangiectasia Group D Complementing (ATDC; also named TRIM29) is highly expressed in many cancer types, including bladder and pancreas. To determine the role of ATDC in tumorigenesis, we developed a novel transgenic mouse model in which ATDC was overexpressed in multiple tissue types. The dominant phenotype in these mice was the development of both papillary and invasive bladder carcinoma beginning at approximately 8 months of age. In this model, invasive bladder tumors were histologically indistinguishable and shared a similar gene expression signature with human invasive bladder cancers. We also found that ATDC was highly expressed in ~70% human bladder cancers where it marked invasive tumors and correlated with worse survival after chemotherapy (p = 0.002). Furthermore, ATDC knockdown decreased proliferation, invasion and tumor growth in multiple human bladder cancer cell lines and in an in vivo orthotopic bladder tumor model. ATDC-induced bladder tumorigenesis was mediated by upregulation of DNA methyltransferase 3A (DNMT3A), which drove PTEN promoter methylation and silencing, events which promoted invasion and proliferation in both transgenic mice and human bladder cancers. These findings establish ATDC as a novel driver and therapeutic target in bladder cancer. In addition, the ATDC transgenic mouse model should serve as an important and unique new model to study bladder cancer development, progression and therapeutic responses. Citation Format: Phillip Palmbos, Lidong Wang, Huibin Yang, Jake LeFlein, John E. Wilkinson, Chandan Kumar-Sinha, L. Priya Kunju, Stephanie Daignault, Xue-Ru Wu, Yair Lotan, Monica Liebert, Mats Ljungman, Diane Simeone. ATDC (Trim29) drives invasive bladder cancer formation. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B24.