T-box transcription factor Brachyury is associated with prostate cancer progress

Neste trabalho desenvolvido no Instituto de Ciências da Vida e da Saúde (ICVS) da Universidade do Minho, em colaboração com os Centros Hospitalares do Porto, e de Alto Ave-Guimarães, assim como IPO do Porto, Filipe Pinto e colaboradores, estudaram o papel biológico e clínico de Brachyury no desenvolvimento de cancro da próstata. Brachyury, é uma proteína fundamental no desenvolvimento embrionário mesodérmico, que em tecidos adultos está ausente. Neste estudo, analisando um grande número de amostras tumorais humanas, foi demonstrado pela primeira vez, que no desenvolvimento do cancro da próstata, há uma expressão anormal da proteína, e que essa expressão estava associada a vários parâmetros de agressividade do tumor, como grau de malignidade e presença de metástases. Estes achados foram posteriormente validados com ensaios in vitro, usando várias linhas celulares de cancro da próstata, onde a presença de Brachyury induziu um aumento do crescimento e da capacidade invasiva das células tumorais, além de promover várias características de malignidade. Este trabalho vem na linha de investigação do coordenador deste estudo, Rui Manuel Reis, que tenta identificar biomarcadores de prognóstico e terapêuticos em tumores humanos, que possam estratificar e futuramente personalizar o tratamento do doente oncológico.

Autores e Afiliações:
Filipe Pinto ^1,2, Nelma Pértega-Gomes ^1,2, Márcia S Pereira ^1,2, José R Vizcaíno ³, Pedro Monteiro ⁴, Rui M Henrique ^5,6,7, Fátima Baltazar ^1,2, Raquel P Andrade ^1,2, Rui M Reis ^1,2,8# 

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/Guimarães, Portugal;  

³ Department of Pathology, Centro Hospitalar do Porto, Portugal;

⁴ Centro Hospitalar do Alto Ave-Guimarães, Portugal;

⁵ Cancer Epigenetics Group – Research Center, Portuguese Oncology Institute-Porto, Porto, Portugal;

⁶ Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences, University of Porto, Porto, Portugal;

⁷ Department of Pathology, Portuguese Oncology Institute - Porto, Porto, Portugal;

⁸ Molecular Oncology Research Center, Barretos Cancer Hospital, S. Paulo, Brazil.

Abstract:
Purpose: Successful therapy of prostate cancer (PCa) patients 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 PCa. 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, PIN lesions, localized tumor and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. Additionally, multiple in vitro models of PCa were used to dissect the biological role of Brachyury in PCa progression. Results: We found that Brachyury is significantly overexpressed in PCa and metastatic tumors when compared to normal tissues, both at protein and mRNA levels. Brachyury expression in the cytoplasm correlate with highly aggressive tumors, while 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, cell cycle regulation and cell metabolism. Conclusions: Collectively, the present study suggests that Brachyury plays an important role in PCa aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor PCa prognosis. Our work paves the way for future studies assessing Brachyury as a possible PCa therapeutic target.

Revista:
Clinical Cancer Research

Link:
http://clincancerres.aacrjournals.org/content/early/2014/07/09/1078-0432.CCR-14-0421.abstract