The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies

Abstract

The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been characterized as a driver of the epithelial-to-mesenchymal switch of human carcinomas. In the current investigation, we present data demonstrating that in two different human lung carcinoma models expression of Brachyury strongly correlates with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. We also demonstrate that chemotherapy treatment in vitro selects for tumor cells with high levels of Brachyury and that the degree of resistance to therapy correlates with the level of Brachyury expression. In vitro and in vivo, human lung carcinoma cells with higher 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 and CDKN1A (p21). Chromatin immunoprecipitation and luciferase reporter assays revealed that Brachyury binds to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapeutic resistance associated with Brachyury expression. Finally, we demonstrate that in vivo treatment of tumor xenografts with chemotherapy results in the selective growth of resistant tumors characterized by high levels of Brachyury expression. Altogether, these results suggest that Brachyury expression may attenuate cell cycle progression, enabling tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas.

T-box Transcription Factor Brachyury Is Associated with Prostate Cancer Progression and Aggressiveness

“…Moreover, depletion of Brachyury in chordoma cells promotes a complete block of cell proliferation (41). An opposite role for Brachyury in cell proliferation was demonstrated in lung and colorectal cell lines by Huang and collaborators, where Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies (15). Therefore, it can be deduced that the role of Brachyury may be tissue-specific or cell-type-dependent.…”

“…Different studies have reported divergent effects of Brachyury expression on cell proliferation. In lung cancer cell lines, it was demonstrated that Brachyury blocks cell-cycle progression and, therefore, mediates tumor resistance (15). However, in adenoid cystic carcinoma cells, Brachyury promoted tumor growth and metastasis formation in vivo (11).…”

The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival

“…Brachyury involvement in cancer was initially limited to chordomas, being currently its main etiological factor [14]. More recently, it has been associated with tumor aggressiveness in several types of cancer cells, ultimately promoting invasion and metastasis [15][16][17][18][19][20][21][22]. Our group has recently described Brachyury as a new and important marker of poor prognosis, cell invasion and metastasis in prostate cancer patients, where it was also associated with higher EMT and stemness expression profiles [19].…”

Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma

“…Recently, Brachyury was demonstrated to induce EMT in human epithelial cells through induction Snail, Slug, and downstream signal [20]. An earlier study on human lung carcinoma cells (in vitro and in vivo) has demonstrated that overexpressed Brachyury divides at slower rates than those with lowexpressed Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb, and CDKN1A (p21) [21]. Another study on oral squamous cell carcinoma cells demonstrated that the expression of Brachyury was correlated with EMT and was significantly associated with lymph node and distant metastasis [22].…”