{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:04:32Z","timestamp":1790085872094,"version":"4.0.1"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273462 82372710 82073199"],"award-info":[{"award-number":["82273462 82372710 82073199"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82503431"],"award-info":[{"award-number":["82503431"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82503478"],"award-info":[{"award-number":["82503478"]}],"id":[{"id":"10.13039\/501100001809","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":[[2026,9,22]]},"abstract":"<jats:p>\n                    Endocrine resistance in ER\n                    <jats:sup>+<\/jats:sup>\n                    breast cancer remains a major clinical challenge. Here, we identify RHAMM as a key driver of resistance by orchestrating polyploid cancer cell (PCC) formation. Single-cell transcriptomics uncovered a G2\/M-enriched, RHAMM\n                    <jats:sup>+<\/jats:sup>\n                    subpopulation in endocrine-resistant tumors. Mechanistically, RHAMM binds Septin9\/10 to promote aberrant cytoskeleton polymerization, activating YAP independent of Hippo signaling, which induces cytokinesis failure and facilitates PCC generation. Concurrently, RHAMM destabilizes p21 mRNA, enabling cell cycle progression despite genomic instability. The RHAMM\u2013p21 axis serves as a bypass mechanism supporting polyploidization. Upon endocrine treatment, RHAMM is transcriptionally up-regulated by Slug. Clinically, RHAMM\n                    <jats:sup>high<\/jats:sup>\n                    signatures are enriched in metastatic and recurrent ER\n                    <jats:sup>+<\/jats:sup>\n                    tumors and correlate with poor prognosis, highlighting its therapeutic relevance. Importantly, targeting RHAMM or YAP abrogates PCC formation and restores fulvestrant sensitivity. These findings reveal RHAMM-mediated polyploidization as an adaptive mechanism underlying endocrine resistance, suggesting the therapeutic potential of targeting the RHAMM\u2013YAP axis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2535342123","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:27Z","timestamp":1789580247000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["RHAMM drives formation of polyploid cancer cells and confers resistance to ER-targeted therapy in breast cancer"],"prefix":"10.1073","volume":"123","author":[{"given":"Shiyi","family":"Wu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, 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Zhao , Cancer cells enter an adaptive persistence to survive radiotherapy and repopulate tumor. Adv. Sci. (Weinh.) 10, e2204177 (2023).","journal-title":"Adv. Sci. (Weinh.)"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf7195"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1589"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.029"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1257-9"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-018-0988-9"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.433"},{"key":"e_1_3_4_44_2","unstructured":"C. Yang RHAMM drives formation of polyploid cancer cells and confer resistance to ER-targeted therapy in breast cancer. 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