Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

Abstract

Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients.

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

“…The immunohistochemistry analyses were performed as previously described (Pinto et al ., , ,b). Representative 4‐μm‐thick sections were subjected to immunohistochemistry analysis according to the streptavidin–biotin–peroxidase complex system (UltraVision Large Volume Detection System Anti‐Polyvalent, HRP; LabVision Corporation), using the primary antibody raised against Brachyury (sc‐20109: Santa Cruz Biotechnology, Inc).…”

“…Brachyury ( T ) is a T‐box transcription factor family with a central role in notochord and mesoderm specification (Herrmann et al ., ). In the last years, Brachyury has been described by us and others to be upregulated in several solid tumors, including chordoma (Vujovic et al ., ), lung (Roselli et al ., ), breast (Palena et al ., ), colorectal (Kilic et al ., ), prostate (Pinto et al ., ) cancer, and GIST (Pinto et al ., ,b). Importantly, in these tumors, Brachyury has been reported as an independent biomarker of poor prognosis (Kilic et al ., ; Haro et al ., ; Palena et al ., ; Pinto et al ., , ,b).…”

“…In the last years, Brachyury has been described by us and others to be upregulated in several solid tumors, including chordoma (Vujovic et al ., ), lung (Roselli et al ., ), breast (Palena et al ., ), colorectal (Kilic et al ., ), prostate (Pinto et al ., ) cancer, and GIST (Pinto et al ., ,b). Importantly, in these tumors, Brachyury has been reported as an independent biomarker of poor prognosis (Kilic et al ., ; Haro et al ., ; Palena et al ., ; Pinto et al ., , ,b). Brachyury acts as a key player in the epithelial–mesenchymal transition (EMT) and metastasis formation (Fernando et al ., ; Imajyo et al ., ; Shimoda et al ., ; Du et al ., ; Palena et al ., ; Pinto et al ., ; Shao et al ., ; Xu et al ., ), also playing an important role in promoting stem cell properties (Sarkar et al ., ; Shimoda et al ., ; Jezkova et al ., ; Pinto et al ., ,b) and resistance to cytotoxic‐based therapy (Fernando et al ., ; Roselli et al ., ; Pinto et al ., ,b).…”

“…Importantly, in these tumors, Brachyury has been reported as an independent biomarker of poor prognosis (Kilic et al ., ; Haro et al ., ; Palena et al ., ; Pinto et al ., , ,b). Brachyury acts as a key player in the epithelial–mesenchymal transition (EMT) and metastasis formation (Fernando et al ., ; Imajyo et al ., ; Shimoda et al ., ; Du et al ., ; Palena et al ., ; Pinto et al ., ; Shao et al ., ; Xu et al ., ), also playing an important role in promoting stem cell properties (Sarkar et al ., ; Shimoda et al ., ; Jezkova et al ., ; Pinto et al ., ,b) and resistance to cytotoxic‐based therapy (Fernando et al ., ; Roselli et al ., ; Pinto et al ., ,b). Based on Brachyury oncogenic behavior, an anti‐Brachyury vaccine (GI‐6301) was developed and is currently in Phase II clinical trial (http://www.clinicaltrials.gov, 2015 – NCT02383498) for patients with chordoma (Heery et al ., ).…”

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

“…The T-box EMT factor Brachyury (an independent biomarker of poor prognosis in prostate cancer patients) has also been shown to promote neuroendocrine differentiation in conjunction with resistance to cytotoxic drugs [70]. Interestingly, EMT has also been implicated downstream of the TMPRSS2-ERG gene fusion event, which is by far the most commonly observed chromosomal rearrangement in prostate tumors [71, 72].…”