Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer
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Filipe Pinto1,2, Nelma Pértega-Gomes3, José R. Vizcaíno4, Raquel P. Andrade5,6, Flavio M. Cárcano7,8 and Rui Manuel Reis1,2,8
1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
2 ICVS/3B’s – PT Government Associate Laboratory, Braga, Portugal
3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
4 Department of Pathology, Centro Hospitalar do Porto, Porto, Portugal
5 CBMR, Centre for Biomedical Research, Universidade do Algarve, Faro, Portugal
6 Regenerative Medicine Program, Department of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal
7 Clinical Oncology Department, Barretos Cancer Hospital, Barretos, S. Paulo, Brazil
8 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, S. Paulo, Brazil
Rui Manuel Reis, email:
Keywords: Brachyury, prostate cancer, therapy resistance
Received: September 21, 2015 Accepted: March 14, 2016 Published: March 31, 2016
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.
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