{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T07:03:50Z","timestamp":1763535830725,"version":"build-2065373602"},"reference-count":73,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"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, K-135475, GINOP-2.3.2-15-2016-00020 and GINOP-2.3.2-15-2016-00034"],"award-info":[{"award-number":["FK-124114, K-135425, K-135475, GINOP-2.3.2-15-2016-00020 and GINOP-2.3.2-15-2016-00034"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006595","name":"Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii","doi-asserted-by":"publisher","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"]}],"id":[{"id":"10.13039\/501100006595","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The New National Excellence Program of the Ministry for Innovation and Technology","award":["\u00daNKP-20-4-SZTE-138"],"award-info":[{"award-number":["\u00daNKP-20-4-SZTE-138"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood\u2013brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors involved in BC brain metastasis formation, focusing on BCCs\u2019 phenotype, growth factor expression, and signaling pathway activation, correlating with BBB alterations and intercellular communication. Hippocampi of female mice inoculated with 4T1 BCCs were examined over time by hematoxylin-eosin, immunohistochemistry and immunofluorescence. Well-established metastases were observed at seven days, increasing thereafter. BCCs entering brain parenchyma presented mesenchymal, migratory, and proliferative features; however, with time, they increasingly expressed epithelial markers, reflecting a mesenchymal\u2013epithelial transition. BCCs also expressed platelet-derived growth factor-B, \u03b24 integrin, and focal adhesion kinase, suggesting autocrine and\/or paracrine regulation with adhesion signaling activation, while balance between Rac1 and RhoA was associated with the motility status. Intercellular communication via gap junctions was clear among BCCs, and between BCCs and endothelial cells. Thrombin accumulation, junctional protein impairment, and vesicular proteins increase reflect BBB alterations related with extravasation. Expression of plasmalemma vesicle-associated protein was increased in BCCs, along with augmented vascularization, whereas pericyte contraction indicated mural cells\u2019 activation. Our results provide further understanding of BC brain metastasis formation, disclosing potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/cancers13040910","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T14:23:27Z","timestamp":1614003807000},"page":"910","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Picturing Breast Cancer Brain Metastasis Development to Unravel Molecular Players and Cellular Crosstalk"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-6883","authenticated-orcid":false,"given":"In\u00eas","family":"Figueira","sequence":"first","affiliation":[{"name":"Farm-ID\u2014Associa\u00e7\u00e3o da Faculdade de Farm\u00e1cia para a Investiga\u00e7\u00e3o e Desenvolvimento, 1649-003 Lisbon, Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa), 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":"T\u00e2nia","family":"Cust\u00f3dio-Santos","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Raquel","family":"Vicente","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0596-2191","authenticated-orcid":false,"given":"Kinga","family":"Moln\u00e1r","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), 6726 Szeged, Hungary"}]},{"given":"Janos","family":"Hask\u00f3","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), 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"}]},{"given":"Mafalda","family":"Videira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmacy, Pharmacology and Health Technologies, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-7337","authenticated-orcid":false,"given":"Imola","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), 6726 Szeged, Hungary"},{"name":"Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania"}]},{"given":"Istv\u00e1n","family":"Krizbai","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH), 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":"Department of Medicine and Pharmaceutical Sciences, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA-Cancer J. 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