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These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44+CD24\u2212\/low. Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3\u20135 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients.<\/jats:p>","DOI":"10.3390\/cells9112442","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T14:10:41Z","timestamp":1605017441000},"page":"2442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer"],"prefix":"10.3390","volume":"9","author":[{"given":"Maria Rita","family":"Dion\u00edsio","sequence":"first","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"},{"name":"Centro Hospitalar de Lisboa Norte, 1649-035 Lisboa, Portugal"}]},{"given":"Andr\u00e9 F.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"Rita","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"In\u00eas","family":"Conde","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"M\u00f3nica","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"Madalena","family":"Gomes","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8521-2904","authenticated-orcid":false,"given":"Marta T.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"},{"name":"In vivo CAM assays, i3S - Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"Pedro","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centro Hospitalar de Lisboa Norte, 1649-035 Lisboa, Portugal"}]},{"given":"Jos\u00e9","family":"Pimentel","sequence":"additional","affiliation":[{"name":"Centro Hospitalar de Lisboa Norte, 1649-035 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6412-8041","authenticated-orcid":false,"given":"Cristiano","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Breast and Gynecologic Oncology, Barretos Cancer Hospital, Barretos-SP 14784-400, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5616-6710","authenticated-orcid":false,"given":"M\u00e1rcia M. C.","family":"Marques","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP 14784-400, Brazil"},{"name":"Barretos School of Health Sciences - FACISB, Barretos-SP 14784-400, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3515-0263","authenticated-orcid":false,"given":"Vin\u00edcius","family":"Duval da Silva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Barretos Cancer Hospital, Barretos-SP 14784-400, Brazil"}]},{"given":"Alison","family":"Barroso","sequence":"additional","affiliation":[{"name":"Department of Breast and Gynecologic Oncology, Barretos Cancer Hospital, Barretos-SP 14784-400, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-7322","authenticated-orcid":false,"given":"Daniel","family":"Preto","sequence":"additional","affiliation":[{"name":"Department of Breast and Gynecologic Oncology, Barretos Cancer Hospital, Barretos-SP 14784-400, Brazil"}]},{"given":"Jorge F.","family":"Cameselle-Teijeiro","sequence":"additional","affiliation":[{"name":"Department of Pathology, Complejo Hospitalario Universit\u00e1rio de Vigo (CHUVI) 36204 Vigo, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-6946","authenticated-orcid":false,"given":"Fernando","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, Faculty of Medicine of Porto University (FMUP), 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9698-9233","authenticated-orcid":false,"given":"Ana Sofia","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1076-1343","authenticated-orcid":false,"given":"Joana","family":"Paredes","sequence":"additional","affiliation":[{"name":"Epithelial Interactions in Cancer (EPIC) group, i3S, Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"IPATIMUP- Institute of Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, Faculty of Medicine of Porto University (FMUP), 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13058-015-0665-1","article-title":"Breast cancer brain metastases: Biology and new clinical perspectives","volume":"18","author":"Witzel","year":"2016","journal-title":"Breast Cancer Res."},{"key":"ref_2","first-page":"4655","article-title":"Recent trends in epidemiology of brain metastases: An overview","volume":"32","author":"Tabouret","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1080\/02841860500486630","article-title":"Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab","volume":"45","author":"Yau","year":"2006","journal-title":"Acta Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1159\/000328679","article-title":"Management of patients with brain metastases receiving trastuzumab treatment for metastatic breast cancer","volume":"34","author":"Witzel","year":"2011","journal-title":"Onkologie"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000338782","article-title":"Biological subtypes and survival outcomes in breast cancer patients with brain metastases (study of the Anatolian Society of Medical Oncology)","volume":"83","author":"Kaplan","year":"2012","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10143-012-0446-6","article-title":"The shifting landscape of metastatic breast cancer to the CNS","volume":"36","author":"Quigley","year":"2013","journal-title":"Neurosurg. 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