Abstract 91: Characterization of Tid1 conditional knockout mice for preclinical testing of novel human head and neck cancer therapeutics

Abstract

Abstract Background: Head and neck cancer (HNC) includes oral cancer (OC). Due to high recurrence, high mortality and resistance to conventional therapies, the development of new chemopreventive agents for HNSCC is an important research priority. Tid1, a DnaJ cochaperone protein, interacts with ErbB family members including EGFR and ErbB2, which function as oncogenes during the tumorigenesis of head and neck cancer and breast cancer. Down regulation of activity or expression level of EGFR and ErbB2 is conversely correlated to expression of Tid1 in head and neck cancer and breast cancer, respectively. In addition, downregulation of Tid1 causes the upregulation of interleukin- 8 (IL-8) to enhance the metastatic ability in breast cancer cells. Transgenic mouse modeling has been an instrumental tool for gene specific physiological and functional study. Additionally, we have demonstrated that Tid1 is important for T cell development and early embryogenesis by established knockout mice systems. Methods: We plan to generate the transgenic mouse models illustrating the head and neck cancer carcinogenesis with our Tid1 knockout mice. Carcinogen administration, drinking water accompanying with 4-NQO (4-Nitroquinoline 1-oxide), has been incorporated within the transgenic mouse modeling along with our Tid1 deficiency mice, at which Tid1 deficiency will be a promoting “hit” during the progression of tumorigenesis with requirement of extra “hits”. Results: Currently, we have successfully established mice with epithelial specific ablation of Tid1 by crossing Tid1flx/flx mice with transgenic K5-Cre mice. Immunohistochemistry or immunefluorescent staining were applied to showed that mutant mice were deficient on Tid1 expression in epidermal layers. Further, the mutant and control mice were subject to carcinogen 4-NQO treatment within drinking water for modeling head and neck cancer progression. Up to date, we discovered that mutant mice treated with 4-NQO displayed faster incident of neoplasia in oral cavity and reduction of body weight in comparison to control mice under same administration. In addition, the histopathological analyses showed that the tumors formed in mutant mice were benign squamous papilloma. Conclusion: These tumors generated in mutant mice exhibited changes in the expression pattern of keratins similar to those observed in human premalignant oral tumors, which are reflective of early stages of tumorigenesis. Therefore, we can further characterize the histopathology and molecular mechanisms of primary or metastatic head and neck cancer development from above mouse models. With the mouse models generated and comprehensiveness with the clinical relevance from our newly identified findings, we will conduct the long-term objectives for the development of therapeutic intervention, which will be based on the above findings to ensure the efficacy of testing drugs at the pre-clinical stage. Citation Format: Jeng-Fan Lo, Li-Hao Cheng. Characterization of Tid1 conditional knockout mice for preclinical testing of novel human head and neck cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 91. doi:10.1158/1538-7445.AM2014-91