{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:51:53Z","timestamp":1791899513876,"version":"4.3.4"},"reference-count":72,"publisher":"National Academy of Sciences","issue":"10","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["DRCMDP-Nov22\/100009"],"award-info":[{"award-number":["DRCMDP-Nov22\/100009"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["224394\/Z\/21\/Z"],"award-info":[{"award-number":["224394\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["P119489"],"award-info":[{"award-number":["P119489"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:p>\n                    Long-term recurrence in breast cancer is driven by reactivation of dormant disseminated tumor cells (DTCs) and remains a major clinical challenge, particularly in estrogen receptor\u2013positive (ER\n                    <jats:sup>+<\/jats:sup>\n                    ) tumors. This process is underpinned by regulation of the cell cycle machinery that controls quiescence maintenance and exit. HES1, a Notch pathway transcription factor, regulates key cell cycle genes and has been shown to demonstrate protein expression oscillations. Here, we sought to establish whether HES1 oscillations may regulate ER+ cancer cell quiescence and reactivation. To investigate this, we developed a fundamental in vitro model of cell cycle arrest and reentry based on reversible CDK4\/6 inhibition (CDK4\/6i) with palbociclib, compatible with quantitative single-cell live-imaging of a knock-in endogenous HES1 reporter. Consistent with earlier findings, HES1 exhibited ~24 h protein oscillations in cycling cells demonstrating a reproducible dip in protein expression prior to S-Phase. During CDK4\/6i-mediated arrest, the ~24 h HES1 oscillation was lost, HES1 levels were maintained at a moderately higher level and HES1 exhibited smaller dips. Similar changes were observed in unperturbed, spontaneously quiescent cells. Following release from CDK4\/6i and cell cycle reentry, these alterations were reversed and the characteristic G1\/S HES1 dip was observed. Preventing this dip at the point of release, by inducibly sustaining HES1 with a Tet-On system, upregulated the cell cycle inhibitor p21, impeded cell cycle reentry and induced cell death. These findings suggest that manipulating HES1 dynamics could represent a promising therapeutic approach to prevent reactivation of dormant tumor cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2520724123","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T20:10:06Z","timestamp":1772482206000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["HES1 oscillations are required for cell cycle reentry in oestrogen receptor\u2013positive breast cancer cells"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8881-8645","authenticated-orcid":false,"given":"Oliver","family":"Cottrell","sequence":"first","affiliation":[{"name":"Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester","place":["Manchester, United 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