The T-box transcription factor Brachyury is emerging as a possible therapeutic target for the treatment of a number of cancer types and patient-
derived studies show that its’ expression in tumours is correlated with a poor prognosis. To date, it has been linked to cancer-associated induction of the epithelial to mesenchymal transition, metastasis of tumour cells and the expression of markers for cancer stem cells. Taken together, these findings indicate that Brachyury may play an important
role in the progression of cancer, although the mechanism through which Brachyury functions is poorly understood. Here we show that Brachyury regulates the potential of colorectal cancer cells to proliferate and reduction in the levels of Brachyury in these cells causes proliferative arrest, and induction of a quiescent-like state through a mechanism that is dependent upon p27Kip1. Additionally, we show that Brachyury regulates the levels of the oncogenic driver c-Myc. We demonstrate that Brachyury enables proliferation, but in
its absence, increased levels of p27Kip1 and decreased levels of c-Myc result in the cessation of proliferation and acquisition of a reversible, quiescent-like state that is distinct from the irreversible proliferative arrest imposed following reduction in the levels of c-Myc alone. We suggest a mechanism whereby Brachyury is required to enable modulation of cell decisions to proliferate or to undergo quiescence. Analysis of patient derived tissue reveals that there are two expressed splice variants of Brachyury, TV1 and TV2. We detected Brachyury in the normal testis and a weak Brachyury expression was observed in a range of normal tissue types. For the first time, our data shows the presence of Brachyury protein in a subset of
secretory lineage cells in the normal colonic crypt, marked by chromogranin A and variably by Lrig1. We hypothesize that these cells might have reserve stem cells properties and Brachyury is involved in the maintenance of intestinal crypt cell plasticity. IHC analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours. Finally, our preliminary work has also identified some intriguing Brachyury-interacting candidate
s that are involved in cancer proliferation and metastasis.