{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:42:01Z","timestamp":1762868521066,"version":"build-2065373602"},"reference-count":72,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-ONC\/29402\/2017, UIDB\/04138\/2020 and UIDP\/04138\/2020, and 441.00 HUNGRIA"],"award-info":[{"award-number":["PTDC\/MED-ONC\/29402\/2017, UIDB\/04138\/2020 and UIDP\/04138\/2020, and 441.00 HUNGRIA"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["FK-124114, K-135425 and K-135475;"],"award-info":[{"award-number":["FK-124114, K-135425 and K-135475;"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Executive Unit for Financing Higher Education, Research, Development and Innovation","award":["PN-III-P1-1.1-TE-2019-1302 and PN-III-P4-ID-PCE-2020-1529"],"award-info":[{"award-number":["PN-III-P1-1.1-TE-2019-1302 and PN-III-P4-ID-PCE-2020-1529"]}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["751547"],"award-info":[{"award-number":["751547"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"La Caixa Foundation","award":["LCF\/PR\/HR19\/52160014"],"award-info":[{"award-number":["LCF\/PR\/HR19\/52160014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.<\/jats:p>","DOI":"10.3390\/ijms22105214","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T10:54:22Z","timestamp":1620989662000},"page":"5214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-6883","authenticated-orcid":false,"given":"In\u00eas","family":"Figueira","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Farm-ID\u2014Associa\u00e7\u00e3o da Faculdade de Farm\u00e1cia para a Investiga\u00e7\u00e3o e Desenvolvimento, 1649-003 Lisbon, Portugal"}]},{"given":"Joana","family":"Godinho-Pereira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Sofia","family":"Galego","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Joana","family":"Maia","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal"},{"name":"Graduate Program in Areas of Basic and Applied Biology, University of Porto, 4099-002 Porto, Portugal"}]},{"given":"J\u00e1nos","family":"Hask\u00f3","sequence":"additional","affiliation":[{"name":"Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), Institute of Biophysics, 6726 Szeged, Hungary"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0596-2191","authenticated-orcid":false,"given":"Kinga","family":"Moln\u00e1r","sequence":"additional","affiliation":[{"name":"Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), Institute of Biophysics, 6726 Szeged, Hungary"}]},{"given":"Rui","family":"Malh\u00f3","sequence":"additional","affiliation":[{"name":"BioISI, BioSystems and Integrative Sciences Institute, Faculty of Sciences, Universidade de Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5932-6211","authenticated-orcid":false,"given":"Bruno","family":"Costa-Silva","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-7337","authenticated-orcid":false,"given":"Imola","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), Institute of Biophysics, 6726 Szeged, Hungary"},{"name":"Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania"}]},{"given":"Istv\u00e1n A.","family":"Krizbai","sequence":"additional","affiliation":[{"name":"Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), Institute of Biophysics, 6726 Szeged, Hungary"},{"name":"Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4649","authenticated-orcid":false,"given":"Maria Alexandra","family":"Brito","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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