{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:52:55Z","timestamp":1790189575953,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-ONC\/28636\/2017 SFRH\/BD\/139178\/2018"],"award-info":[{"award-number":["PTDC\/MED-ONC\/28636\/2017 SFRH\/BD\/139178\/2018"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The receptor activator of the nuclear factor-\u03baB ligand (RANKL)\/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL\/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL\/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL\/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.<\/jats:p>","DOI":"10.3390\/cells10081978","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T08:47:52Z","timestamp":1628066872000},"page":"1978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The Roadmap of RANKL\/RANK Pathway in Cancer"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-4477","authenticated-orcid":false,"given":"Sandra","family":"Casimiro","sequence":"first","affiliation":[{"name":"Luis Costa Laboratory, Instituto de Medicina Molecular\u2014Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Vilhais","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-0821","authenticated-orcid":false,"given":"In\u00eas","family":"Gomes","sequence":"additional","affiliation":[{"name":"Luis Costa Laboratory, Instituto de Medicina Molecular\u2014Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Costa","sequence":"additional","affiliation":[{"name":"Luis Costa Laboratory, Instituto de Medicina Molecular\u2014Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Oncology Division, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-028 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1101\/gad.13.18.2412","article-title":"RANK is essential for osteoclast and lymph node development","volume":"13","author":"Dougall","year":"1999","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1073\/pnas.95.7.3597","article-title":"Osteoclast differentiation factor is a ligand for osteoprotegerin\/osteoclastogenesis-inhibitory factor and is identical to TRANCE\/RANKL","volume":"95","author":"Yasuda","year":"1998","journal-title":"Proc. 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