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

Abstract

Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer.Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression.Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cellcycle regulation, and cell metabolism.Conclusions: Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target. Clin Cancer Res; 20(18); 4949-61. Ó2014 AACR.

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

“…*p \ 0.05. NS non significant to its role in the EMT process and involvement in metastatic development in solid tumors [17,19], Brachyury is positioned as a promising therapeutic target for advanced cancer patients [40,44]. To our knowledge, this is the first study that investigates Brachyury immunostaining and its relevance as a novel marker of aggressiveness in GIST.…”

“…We previously showed that molecular alterations in RKIP [39] and MCT1 and its chaperone (CD147) [24] are associated with GIST poor overall survival, but do not aid in predicting tumor resistance or metastatic disease, which can preclude patient treatment. T-box transcription factor Brachyury was recently described to be overexpressed in several tumor types [17-20, 40, 41], playing an important role in EMT processes, metastasis and stem cell-like features [15][16][17][18][19][41][42][43]. Due Fig.…”

“…Representative 4-lm-thick sections were subjected to immunohistochemical analysis using the streptavidin-biotin peroxidase complex system (UltraVision Large Volume Detection System Anti-Polyvalent, HRP; LabVision Corp.), as previously described [19] (Supplementary Fig S1), using the primary antibody raised against Brachyury (sc-20109: Santa Cruz Biotechnology, Inc.) [16,19,[27][28][29]. Tumor samples were evaluated for extension (percentage of cytoplasm-positive cells: 0, negative; 1, \25 % positive cells; 2, 26-50 % positive cells; 3, [50 % positive cells) and intensity (0, negative; 1, weak; 2, moderate; 3, strong) of the immunoreactions.…”

“…Microarray coexpression studies in five GIST samples were extracted from Subramanian data set [34]. Microarray expression profiles were clustered by functional importance and signaling pathways using DAVID v6.7 bioinformatic tool (The Database for Annotation, Visualization and Integrated Discovery) [35,36], as previously described [19].…”

“…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]. Taking into account the important role of Brachyury in tumorigenesis and the need for new biomarkers in GIST, we aimed to examine whether Brachyury immunostaining is associated with GIST prognosis and aggressiveness.…”