{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:17:12Z","timestamp":1773937032892,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Despite advances in targeted therapies, resistance to anti\u2010human epidermal growth factor receptor 2 (HER2) treatments remains a significant challenge in breast cancer (BC) management. This study aimed to evaluate the effectiveness of a triple\u2010targeting regimen\u2014Denosumab (D), Pertuzumab (P) and Trastuzumab (T)\u2014for HER2\u2010positive (HER2\n                    <jats:sup>+<\/jats:sup>\n                    ) BC, and to assess the added value of immune checkpoint inhibitors (ICIs). Immunohistochemical analysis of 120 paraffin\u2010embedded BC samples revealed that HER2\n                    <jats:sup>+<\/jats:sup>\n                    tumours exhibited significantly higher receptor activator of nuclear factor (NF)\u2010\u03baB (RANK) expression compared to HER2\u2010negative (HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) tumours. Notably, RANK\u2010positive (RANK\n                    <jats:sup>+<\/jats:sup>\n                    )\/HER2\n                    <jats:sup>+<\/jats:sup>\n                    patients who received triple\u2010targeting therapy experienced a statistically significant improvement in disease\u2010free survival (DFS), while RANK\u2010negative (RANK\n                    <jats:sup>\u2212<\/jats:sup>\n                    )\/HER2\n                    <jats:sup>+<\/jats:sup>\n                    patients did not derive similar benefit. In BT\u2010474 HER2\n                    <jats:sup>+<\/jats:sup>\n                    xenograft mouse models, the combination of D+P+T significantly reduced tumour volume and weight. Additional analyses showed elevated\n                    <jats:italic>signal transducer and activator of transcription 3<\/jats:italic>\n                    (\n                    <jats:italic>STAT3<\/jats:italic>\n                    ) expression in HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    tissues and higher\n                    <jats:italic>mechanistic target of rapamycin<\/jats:italic>\n                    (\n                    <jats:italic>mTOR<\/jats:italic>\n                    ) expression in HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    compared to HER2\n                    <jats:sup>+<\/jats:sup>\n                    samples. Importantly, three\u2010dimensional (3D) cell culture experiments demonstrated that adding ICIs (Nivolumab (N) and Ipilimumab (I)) to the triple\u2010targeting regimen further reduced cell viability in HER2\n                    <jats:sup>+<\/jats:sup>\n                    BC cells. These results underscore the pivotal role of the RANK\u2013receptor activator of NF\u2010\u03baB ligand (RANKL) axis in tumour growth and immune regulation, supporting the use of triple\u2010targeting therapy and suggesting enhanced benefits with the inclusion of ICIs to potentially overcome therapeutic resistance in HER2\n                    <jats:sup>+<\/jats:sup>\n                    BC.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71071","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:31:56Z","timestamp":1772973116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of\n                    <scp>HER2<\/scp>\n                    and\n                    <scp>RANK<\/scp>\n                    in Breast Cancer and New Therapeutic Approaches With Denosumab, Anti\u2010HER2 Antibodies and Immunotherapy"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-7905","authenticated-orcid":false,"given":"Panagiotis","family":"Sarantis","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aristofania","family":"Simatou","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-0575","authenticated-orcid":false,"given":"Ioanna A.","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kostas","family":"Palamaris","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical School National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni\u2010Myrto","family":"Trifylli","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine\u2014GI\u2010Liver Unit, General Hospital \u2018Hippokratio\u2019, Medical School National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Koustas","sequence":"additional","affiliation":[{"name":"Oncology Department General Hospital \u2018Evangelismos\u2019  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Piperi","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Medical School 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