{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:34:39Z","timestamp":1785418479465,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,15]]},"group-title":"Cancer Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01CA272621"],"award-info":[{"award-number":["R01CA272621"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Despite continuous progress in diagnosis and therapy, breast carcinoma (BC) remains a major health problem. Triple-negative (Estrogen Receptor-\/Progesterone Receptor-\/HER2-) breast cancer (TNBC) is the most aggressive subtype due to its high metastatic potential and resistance to chemotherapy. The Y-box binding protein 1 (YB-1) transcription factor, a protein present in both cytoplasm and nucleus, is a driver of TNBC malignancy as it stimulates its cancer stem cell phenotype and disrupts cell cycle progression. Here, we hypothesized that YB-1-containing sEVs deliver YB-1 to the nuclear compartment of recipient cancer cells and play a major role in the activation of the metastatic process. We found a selective enrichment of YB-1 in sEVs from MDA and 4T1 cells, with \u223c65% and 50% of all sEVs positive for YB-1 by d-STORM. Administration of sEVs from wild-type MDA and 4T1 to their YB-1 knockout counterparts resulted in nuclear translocation of sEV-associated YB-1 and increased tumorsphere formation. Pharmacological blockade of the nuclear transport machinery based on the inhibition of the formation of the \u201cVOR\u201d complex (\n                  <jats:underline>V<\/jats:underline>\n                  AP-A-\n                  <jats:underline>O<\/jats:underline>\n                  RP3-\n                  <jats:underline>R<\/jats:underline>\n                  ab7) by PRR851 impaired both nuclear translocation and the YB-1-induced increase in tumorsphere formation. YB-1 phosphorylation at S102 was required for nuclear localization. In fact, loss of YB-1 phosphorylation inhibited tumorsphere growth and stemness of cancer cells and YB-1-positive sEVs restored the oncogenic behavior of cancer cells expressing phospho-mutant YB-1. Moreover, PRR851 inhibited the nuclear translocation of the phosphorylated form of YB-1 and the oncogenic behavior of the TNBC cells. These data support the conclusion that the nuclear translocation of sEV-associated phosphorylated YB-1 is an important factor in the malignant behavior of TNBC and a potential therapeutic target.\n                <\/jats:p>","DOI":"10.64898\/2026.07.14.738446","type":"posted-content","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T09:30:16Z","timestamp":1784107816000},"source":"Crossref","is-referenced-by-count":0,"title":["Nuclear translocation of phosphorylated YB-1 via small extracellular vesicles contributes to the malignant phenotype of triple negative breast cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6347-8576","authenticated-orcid":false,"given":"Mark F.","family":"Santos","sequence":"first","affiliation":[{"name":"Touro University Nevada College of Medicine, Henderson, Nevada, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9349-1763","authenticated-orcid":false,"given":"Yeaji","family":"Kim","sequence":"additional","affiliation":[{"name":"The MetroHealth System, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Biebighauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0644-7375","authenticated-orcid":false,"given":"Aurelio","family":"Lorico","sequence":"additional","affiliation":[{"name":"Touro University Nevada College of Medicine, Henderson, Nevada, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-7633","authenticated-orcid":false,"given":"Khalid","family":"Sossey-Alaoui","sequence":"additional","affiliation":[{"name":"The MetroHealth System, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071714201814000_2026.07.14.738446v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70043"},{"key":"2026071714201814000_2026.07.14.738446v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/35021093"},{"key":"2026071714201814000_2026.07.14.738446v1.3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13246262"},{"key":"2026071714201814000_2026.07.14.738446v1.4","unstructured":"Wang W KY , Zhao X , Weber Bonk , Keri R , Su B , Sossey-Alaoui K . The small molecule inhibitor SU056-mediated targeting of YB1 inhibits the Rb pathway in triple negative breast cancer tumors. Breast Cancerr Research 2026;Under Revision(NA):NA."},{"key":"2026071714201814000_2026.07.14.738446v1.5","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201211138"},{"key":"2026071714201814000_2026.07.14.738446v1.6","doi-asserted-by":"publisher","DOI":"10.4103\/JLP.JLP_58_18"},{"key":"2026071714201814000_2026.07.14.738446v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nm0497-447"},{"key":"2026071714201814000_2026.07.14.738446v1.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003725"},{"key":"2026071714201814000_2026.07.14.738446v1.9","doi-asserted-by":"crossref","first-page":"e12132","DOI":"10.1002\/jev2.12132","article-title":"Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum","volume":"10","year":"2021","journal-title":"J Extracell Vesicles"},{"key":"2026071714201814000_2026.07.14.738446v1.10","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14804"},{"key":"2026071714201814000_2026.07.14.738446v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40227-8"},{"key":"2026071714201814000_2026.07.14.738446v1.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1014224"},{"key":"2026071714201814000_2026.07.14.738446v1.13","doi-asserted-by":"publisher","DOI":"10.1042\/BST20253005"},{"key":"2026071714201814000_2026.07.14.738446v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107589"},{"key":"2026071714201814000_2026.07.14.738446v1.15","doi-asserted-by":"publisher","DOI":"10.3390\/cells14131034"},{"key":"2026071714201814000_2026.07.14.738446v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-024-03166-2"},{"key":"2026071714201814000_2026.07.14.738446v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"2026071714201814000_2026.07.14.738446v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12132"},{"key":"2026071714201814000_2026.07.14.738446v1.19","doi-asserted-by":"publisher","DOI":"10.20517\/evcna.2023.46"},{"key":"2026071714201814000_2026.07.14.738446v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-025-03177-0"},{"key":"2026071714201814000_2026.07.14.738446v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.70060"},{"key":"2026071714201814000_2026.07.14.738446v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.365"},{"key":"2026071714201814000_2026.07.14.738446v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2021.110073"},{"key":"2026071714201814000_2026.07.14.738446v1.24","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.22009"},{"key":"2026071714201814000_2026.07.14.738446v1.25","doi-asserted-by":"publisher","DOI":"10.2217\/14796694.5.2.153"},{"key":"2026071714201814000_2026.07.14.738446v1.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0945"},{"key":"2026071714201814000_2026.07.14.738446v1.27","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2202"},{"key":"2026071714201814000_2026.07.14.738446v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208590"},{"key":"2026071714201814000_2026.07.14.738446v1.29","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12102795"},{"key":"2026071714201814000_2026.07.14.738446v1.30","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71982"},{"key":"2026071714201814000_2026.07.14.738446v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-07509-6"},{"key":"2026071714201814000_2026.07.14.738446v1.32","first-page":"49","article-title":"YB-1 is a Transcription\/Translation Factor that Orchestrates the Oncogenome by Hardwiring Signal Transduction to Gene Expression","volume":"2","year":"2007","journal-title":"Transl Oncogenomics"},{"key":"2026071714201814000_2026.07.14.738446v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/s43046-025-00322-x"},{"key":"2026071714201814000_2026.07.14.738446v1.34","doi-asserted-by":"publisher","DOI":"10.1515\/bmc-2022-0024"},{"key":"2026071714201814000_2026.07.14.738446v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-48064-w"},{"key":"2026071714201814000_2026.07.14.738446v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/s40659-023-00477-8"},{"key":"2026071714201814000_2026.07.14.738446v1.37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010212"},{"key":"2026071714201814000_2026.07.14.738446v1.38","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-024-02191-2"},{"key":"2026071714201814000_2026.07.14.738446v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2019.11.007"},{"key":"2026071714201814000_2026.07.14.738446v1.40","doi-asserted-by":"publisher","DOI":"10.20517\/evcna.2023.37"},{"key":"2026071714201814000_2026.07.14.738446v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.11.024"},{"key":"2026071714201814000_2026.07.14.738446v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.01.043"},{"key":"2026071714201814000_2026.07.14.738446v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0036-9"},{"key":"2026071714201814000_2026.07.14.738446v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaf227"},{"key":"2026071714201814000_2026.07.14.738446v1.45","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4056"},{"key":"2026071714201814000_2026.07.14.738446v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.04.011"},{"key":"2026071714201814000_2026.07.14.738446v1.47","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2156"},{"key":"2026071714201814000_2026.07.14.738446v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.02.014"},{"key":"2026071714201814000_2026.07.14.738446v1.49","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0648"},{"key":"2026071714201814000_2026.07.14.738446v1.50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1330868"},{"key":"2026071714201814000_2026.07.14.738446v1.51","doi-asserted-by":"publisher","DOI":"10.1111\/ajco.14095"},{"key":"2026071714201814000_2026.07.14.738446v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216495"},{"key":"2026071714201814000_2026.07.14.738446v1.53","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-25-1240"},{"key":"2026071714201814000_2026.07.14.738446v1.54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1703697"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.14.738446","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T21:20:24Z","timestamp":1784323224000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.14.738446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":54,"URL":"https:\/\/doi.org\/10.64898\/2026.07.14.738446","relation":{},"subject":[],"published":{"date-parts":[[2026,7,15]]},"subtype":"preprint"}}