{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:47:48Z","timestamp":1791910068486,"version":"4.3.4"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Breast Cancer Now","award":["2019AugPR1320"],"award-info":[{"award-number":["2019AugPR1320"]}],"id":[{"id":"https:\/\/ror.org\/02qa92s63","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Triple negaJve breast cancer (TNBC) is characterised by poor prognosis and limited treatment opJons, parJally due to therapy-resistant stem\/progenitor cells driving metastasis. Elevated expression of the transcripJon factor MYBL2 is associated with aggressive disease, yet its role in BC stem\/progenitor cells remains elusive. Here, we employed inducible MYBL2 downregulaJon in TNBC cell lines and paJent-derived models to invesJgate its funcJon and idenJfy potenJal vulnerabiliJes associated with its high expression. Our funcJonal and mechanisJc analyses reveal that high MYBL2 levels are criJcal for stem cell self-renewal, DNA repair, and replicaJon stress response and lowering MYBL2 impairs stemness and self-renewal both in vitro and in vivo. Accordingly, high-MYBL2 stem\/progenitor cells exhibit increased sensiJvity to Pol\u03b8 inhibitors which is lost upon MYBL2 downregulaJon due to transcripJonal suppression. Combining Pol\u03b8 inhibitors with ATR inhibitors further enhances this sensiJvity, in vitro, ex vivo and in vivo. These findings suggest that dual Pol\u03b8\/ATR inhibiJon represents a promising therapeuJc strategy to target TNBC stem\/progenitor cells with high MYBL2 expression, highlighJng MYBL2 as a potenJal biomarker to straJfy paJents for Pol\u03b8 inhibitor-based therapies in TNBC.<\/jats:p>","DOI":"10.1172\/jci202898","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:37Z","timestamp":1791907237000},"source":"Crossref","is-referenced-by-count":0,"title":["Combined inhibition of DNA Polymerase Theta and ATR targets MYBL2-high triple-negative breast cancer stem cells"],"prefix":"10.1172","author":[{"given":"Rachel","family":"Bayley","sequence":"first","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrija","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menna","family":"Shamma","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga","family":"Koscielniak","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Munsey","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Stiby","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohdana-Myroslava","family":"Briantseva","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirendeep","family":"Jawanda","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3226-0515","authenticated-orcid":true,"given":"Christopher J.","family":"Lord","sequence":"additional","affiliation":[{"name":"Precision Oncology Laboratory, The Breast Cancer Now Toby Robins Research Centre, The InsJtute of Cancer Research, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer M.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Saponaro","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme C. M.","family":"Smith","sequence":"additional","affiliation":[{"name":"ArJos Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, Edgbaston, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,13]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/202898\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:38Z","timestamp":1791907238000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/202898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":0,"alternative-id":["10.1172\/JCI202898"],"URL":"https:\/\/doi.org\/10.1172\/jci202898","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]}}}