Our laboratory has identified the T-box transcription factor brachyury as a driver of EMT in human carcinomas. We have shown that high levels of expression of this molecule result in the acquisition of tumor cell motility and invasiveness in vitro and facilitate metastatic dissemination in vivo in animal models of cancer. We have now demonstrated that the level of brachyury expression in human carcinoma cells directly correlates with resistance to cytotoxic treatments, including chemotherapy and radiation, and that treatment in vitro or in vivo with cycles of chemotherapy selects for a population of highly mesenchymal, invasive and brachyury positive tumor cells. By conducting detailed mechanistic studies we have shown that brachyury is able to mediate resistance to cell death via modulation of cell cycle progression and mitigation of p53-mediated DNA damage responses. Due to its relevant role in cancer metastasis and resistance, and its potential as a cancer target, we have studied in detail the pattern of expression of brachyury across a range of human tissues. Our results demonstrated that brachyury is preferentially expressed in human carcinomas, including lung, breast and colon, while being absent in the majority of normal tissues evaluated, with the exception of some levels detected in normal testis and some thyroid tissues. We recently conducted a comprehensive study of brachyury expression in breast carcinomas and have demonstrated that this EMT driver is overexpressed in primary as well as metastatic breast cancer tissues, and that high levels of brachyury mRNA in primary breast tumors correlate with poor clinical outcome in patients treated with tamoxifen therapy post-surgery. We have recently developed a yeast-recombinant vector expressing the full-length brachyury protein and demonstrated its ability to elicit CD4+ and CD8+ brachyury-specific T-cell immune responses in vivo in animal models as well as in vitro with human T cells. The brachyury-specific T cells, in turn, were shown to lyse target tumor cells that express the brachyury protein. These results formed the rationale for a currently ongoing Phase I clinical trial of yeast-brachyury vaccine in patients with advanced carcinomas. We have made the paradoxical observation that reducing, rather than increasing, the level of the target brachyury in some carcinoma cells enhances their cytotoxic response to brachyury-specific T cells. This observation was expanded to demonstrate that tumor cells with very high levels of brachyury may be less sensitive to various immune effector cells, including antigen-specific T cells, NK, LAK cells or the immune mediators FasL and TRAIL, than tumor cells with intermediate or low levels of brachyury. Studies are ongoing to identify strategies aimed at reducing brachyury and mesenchymal features to render tumor cells more susceptible to immune attack.
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