Many Roles of Transcriptional Factor Brachyury

Brachyury gene, firstly discovered in 1927, encodes a protein of 435 amino acids, which functions as a transcription factor regulating posterior mesoderm formation and notochord differentiation, and plays many roles in carcinogenesis and other some biological process.

Brachyury in notochord formation and notochord cell-derived cells

Brachyury is essential to maintain notochord cell fate and function [1]. Chordoma is a rare malignant tumor originated from notochordal cell rests. Chordoma patients with higher Brachyury expression showed significantly shorter progression-free survival. Brachyury was suggested as a prognostic biomarker in chordoma. Further Brachyury was found to promote chordoma cell growth via PI3K/Akt signaling [2]. The origin of intervertebral disc cells is always considered to be associated with notochord cells. Brachyury was found to have the capability of reprogramming degenerative human intervertebral disc cells to a healthy phenotype [3]. Our research has also found that Brachyury can protect the intervertebral disc cells from degeneration.

Brachyury promotes tumor cells invasiveness in various types of cancers

Brachyury also plays an important role in the development of many epithelium origin tumors. In lung cancer patients, high expression of the Brachyury protein was significantly associated with poor prognosis [4]. Our previous study indicated that Brachyury promotes tumor cells proliferation and inhibits apoptosis in Non-Small Cell Lung Cancer (NSCLC) H460 cells [5].

In breast cancer, nuclear expression of Brachyury is an independent marker that predicts poor prognosis [6]. Brachyury is reported to be overexpressed in triple negative breast cancer and mediates epithelial-mesenchymal transition [7,8]. Brachyury is also associated with chemotherapy resistance in breast cancer [9]. Our previous study indicated that Brachyury could promote breast cancer metastasis to bone. SOX5 knockdown in Brachyury-expressing breast cancer cells resulted in a significant reduction in survival and tumorigenic capabilities in the bone microenvironment [10]. In gastrointestinal stromal tumors, Brachyury can lead to aggressiveness and poor survival [11]. High Brachyury expression is associated with metastasis and poor prognosis in oral squamous cell carcinoma. Brachyury synergistically promotes self-renewal and invasiveness with other transcriptional factor in oral cancer cells, which is expected to develop into specific therapeutic targets [12,13]. Brachyury has been reported to involve in the progression of prostate cancer and contributes to tumor chemotherapy resistance [14]. Brachyury also plays an oncogenic role in testicular germ cell tumors and its nuclear localization is suggested as a novel biomarker of poor prognosis [15].

In conclusion, Brachyury has become an attractive therapeutic target not only in various types of cancers but also in regenerative medicine. The thorough investigation of the upstream and downstream regulatory pathways of Brachyury in different contexts will facilitate the development of related drugs or other therapeutic strategies.

This work was supported by Scientific research project of Wuxi Health Commission (Grant No. Q202006). No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

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