Abstract 1489: The T-box transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to chemotherapy and radiation

The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been proposed as a significant determinant of the epithelial-mesenchymal transition (EMT) in human carcinomas. In the current investigation, we present data demonstrating that in three different human lung carcinoma models, expression of Brachyury is associated with a mesenchymal phenotype. Additionally, elevated Brachyury expression is shown to strongly correlate with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. Further investigation showed that chemotherapy treatment in vitro selected tumor cells that were high in Brachyury, and that the degree of resistance to therapy was comparable to the level of Brachyury expression. We also demonstrate that in vitro and in vivo, human lung carcinoma cells with greater levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb (pRb), and CDKN1A (p21). ChIP and luciferase resporter assays revealed that Brachyury represses p21 expression in carcinoma cells by directly binding to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapy resistance associated with Brachyury expression. Finally, we observed that in vivo treatment of tumor xenografts with chemotherapy resulted in the selective growth of resistant tumors that were high in Brachyury. Altogether, these results suggest that in addition to being a driver of EMT, Brachyury expression may attenuate cell cycle progression, and enable tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas. Citation Format: Bruce K. Huang, Joseph Cohen, Romaine I. Fernando, Duane H. Hamilton, Mary T. Litzinger, James W. Hodge, Claudia M. Palena. The T-box transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to chemotherapy and radiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1489. doi:10.1158/1538-7445.AM2013-1489