{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:38:11Z","timestamp":1790645891548,"version":"4.1.0"},"reference-count":228,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81902701"],"award-info":[{"award-number":["81902701"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Liaoning Province under Grant","award":["2023JH2\/20200036"],"award-info":[{"award-number":["2023JH2\/20200036"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Estrogen receptor-positive (ER+) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER+ tumors eventually develop resistance, culminating in distant metastases\u2014most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K\/AKT\/mTOR, TGF-\u03b2, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER+ breast cancer, with a particular focus on tumor\u2013bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4\/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER+ breast cancer with bone involvement.<\/jats:p>","DOI":"10.3390\/ijms27020785","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:52:57Z","timestamp":1768319577000},"page":"785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bone Metastasis in Estrogen Receptor-Positive Breast Cancer: Molecular Insights and Therapeutic Advances"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9356-0411","authenticated-orcid":false,"given":"Zhuoran","family":"Huang","sequence":"first","affiliation":[{"name":"School of Medicine, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathogenic Biology, Shenyang Medical College, Shenyang 110034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-9247","authenticated-orcid":false,"given":"Yanshu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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