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

2016-05Journal article Open access
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dc.contributor.authorPinto, Filipe
dc.contributor.authorPertega-Gomes, Nelma
dc.contributor.authorVizcaino, Jose R.
dc.contributor.authorAndrade, Raquel P.
dc.contributor.authorCarcano, Flávio M.
dc.contributor.authorReis, Rui Manuel
dc.date.accessioned2017-04-07T15:56:39Z
dc.date.available2017-04-07T15:56:39Z
dc.date.issued2016-05
dc.description.abstractProstate 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.
dc.identifier.doi10.18632/oncotarget.8499
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/10400.1/9483
dc.language.isoeng
dc.peerreviewedyes
dc.relationLEARNING FROM THE EMBRYO: UNDERSTANDING EARLY EMBRYONIC T GENE – BRACHYURY - IMPACT IN HUMAN TUMORIGENESIS
dc.relation.isbasedonWOS:000377742600011
dc.titleBrachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleLEARNING FROM THE EMBRYO: UNDERSTANDING EARLY EMBRYONIC T GENE – BRACHYURY - IMPACT IN HUMAN TUMORIGENESIS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F81369%2F2011/PT
oaire.citation.endPage28902
oaire.citation.issue20
oaire.citation.startPage28891
oaire.citation.titleOncotarget
oaire.citation.volume7
oaire.fundingStream5876
person.familyNameAndrade
person.givenNameRaquel
person.identifier.ciencia-id2312-360B-227A
person.identifier.orcid0000-0002-0397-5917
person.identifier.scopus-author-id7103114918
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublication.latestForDiscoveryf2d3fc39-a8f6-4d83-9e60-2e2fdfbc2b4a
relation.isProjectOfPublicatione13142f2-37b8-4b5a-b2cd-352e62003184
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