{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:08:53Z","timestamp":1792591733156,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010271","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000}}],"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["ZIA BC 005445"],"award-info":[{"award-number":["ZIA BC 005445"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The TGF-\u03b2-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that\n                    <jats:italic>CLIC4<\/jats:italic>\n                    expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated\n                    <jats:italic>CLIC4<\/jats:italic>\n                    predicted poor outcome in breast cancer patients and was linked to the TGF-\u03b2 pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host\n                    <jats:italic>Clic4<\/jats:italic>\n                    in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of\n                    <jats:italic>Clic4<\/jats:italic>\n                    retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010271","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T13:38:31Z","timestamp":1655818711000},"page":"e1010271","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8580-3480","authenticated-orcid":true,"given":"Vanesa C.","family":"Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9291-631X","authenticated-orcid":true,"given":"Howard H.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-6231","authenticated-orcid":true,"given":"Alayna","family":"Craig-Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-7715","authenticated-orcid":true,"given":"Wendy","family":"Dubois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0717-6917","authenticated-orcid":true,"given":"Brandi L.","family":"Carofino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Lack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Dwyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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Singh","year":"2010","journal-title":"FEBS Lett"},{"issue":"2","key":"pgen.1010271.ref003","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.bbamem.2013.05.025","article-title":"CLIC proteins, ezrin, radixin, moesin and the coupling of membranes to the actin cytoskeleton: a smoking gun?","volume":"1838","author":"L Jiang","year":"2014","journal-title":"Biochim Biophys Acta"},{"issue":"22","key":"pgen.1010271.ref004","doi-asserted-by":"crossref","first-page":"4165","DOI":"10.1242\/jcs.189795","article-title":"Emerging biological roles of Cl- intracellular channel proteins","volume":"129","author":"E Argenzio","year":"2016","journal-title":"J Cell Sci"},{"issue":"96","key":"pgen.1010271.ref005","article-title":"Intracellular Chloride Channels: Novel Biomarkers in Diseases.","volume":"11","author":"S Gururaja Rao","year":"2020","journal-title":"Frontiers in 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