{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:07Z","timestamp":1792790407297,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Cancer Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences","award":["1R16GM145545"],"award-info":[{"award-number":["1R16GM145545"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["U54 AA019765"],"award-info":[{"award-number":["U54 AA019765"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Minority Health and Health Disparities","award":["U54 MD012392"],"award-info":[{"award-number":["U54 MD012392"]}],"id":[{"id":"https:\/\/ror.org\/0493hgw16","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  ErbB2 overexpression occurs in 15\u201320% of invasive breast cancer (BC) and inactivation of Cyclin D1-CDK4\/6 axis reduce mammary stem\/progenitor cells in ErbB2-driven tumorigenesis. Here, we explored the preventive role of short-term palbociclib intervention in MMTV-ErbB2 mice. Palbociclib significantly inhibited the proliferation and stemness of ErbB2-overexpressed BC cells in vitro and in vivo. Furthermore, short-term palbociclib exposure during the early premalignant risk window significantly delayed mammary tumor development and reduced tumor multiplicity, accompanied by the suppression of epithelial proliferation and ductal\/alveolar morphogenesis in premalignant tissues, as well as prolonged tumor-free survival compared with controls. Importantly, palbociclib reduced the luminal epithelial (CD24\n                  <jats:sup>high<\/jats:sup>\n                  \/CD49f\n                  <jats:sup>low<\/jats:sup>\n                  ), mammary reconstitution unit-enriched (CD24\n                  <jats:sup>high<\/jats:sup>\n                  \/CD49f\n                  <jats:sup>high<\/jats:sup>\n                  ) subpopulations, and luminal progenitor\/TIC-enriched (CD61\n                  <jats:sup>high<\/jats:sup>\n                  \/CD49f\n                  <jats:sup>mid<\/jats:sup>\n                  ) subpopulations. These changes were accompanied by diminished mammary epithelial cell stemness functions, including colony-forming, mammosphere-forming, and 3D growth activities of mammary epithelial cells. Mechanistically, palbociclib-treated tissues showed inhibition of the Cyclin D1-CDK4\/6-RB-E2F axis and coordinated attenuation of ER-, ErbB2- and Wnt\/\u03b2-catenin-associated signaling. Together, we demonstrate that short-term CDK4\/6 inhibition during a premalignant risk window produces a sustained delay in ErbB2-driven mammary tumorigenesis, associated with remodeling of the mammary epithelial hierarchy and suppression of proliferative and stem\/progenitor-associated activity, suggesting CDK4\/6 inhibition as a strategy for ErbB2-positive BC prevention.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphic Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"751306v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.14.751306","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:00:17Z","timestamp":1789646417000},"source":"Crossref","is-referenced-by-count":0,"title":["Risk-Window Palbociclib Exposure Delays ErbB2-Driven Mammary Tumorigenesis and Suppresses Mammary Epithelial Cell Stemness"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7686-5889","authenticated-orcid":false,"given":"Yongxuan","family":"Liu","sequence":"first","affiliation":[{"name":"Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Luoyang Cancer Hospital, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China"},{"name":"Julius L. Chambers Biomedical\/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC, 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B.","family":"Parris","sequence":"additional","affiliation":[{"name":"Julius L. Chambers Biomedical\/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC, 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikun","family":"Ma","sequence":"additional","affiliation":[{"name":"Julius L. 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