{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:38:01Z","timestamp":1775083081778,"version":"3.50.1"},"reference-count":49,"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":["82203641"],"award-info":[{"award-number":["82203641"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"R&D Program of Beijing Municipal Education Commission","award":["KM202310025024"],"award-info":[{"award-number":["KM202310025024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bone metastasis in breast cancer remains a major therapeutic challenge because current osteoclast-targeted therapies do not fully disrupt the tumor\u2013bone vicious cycle. Osteocytes, the most abundant bone cells, are increasingly recognized as key regulators of bone\u2013tumor crosstalk. Previous work has shown that osteocyte-specific overexpression of the Wnt co-receptor LRP5 inhibits breast cancer-induced osteolysis and generates conditioned medium (CM) with tumor-suppressive activity. Proteomic analysis identified LIM domain and actin-binding protein 1 (LIMA1) as a central mediator that interacts with Myosin Vb (MYO5B), suggesting the role of the LIMA1\/MYO5B regulatory axis. This study demonstrates that CM derived from LRP5-overexpressing osteocytes suppresses EO771 breast cancer cell proliferation, migration, and invasion, and downregulates tumor-promoting proteins, including MMP9, Snail, IL-6, and TGF-\u03b21, while upregulating the apoptosis-related protein cleaved caspase-3. These effects were largely reversed by knockdown of LIMA1 or MYO5B. In syngeneic mouse models of mammary tumors and bone metastasis, systemic administration of LRP5-overexpressing osteocyte-derived CM reduced tumor burden and osteolytic bone destruction, whereas genetic knockdown of LIMA1 in osteocytes or MYO5B in tumor cells abrogated these protective effects. Collectively, these findings indicate that LRP5 activation in osteocytes engages the LIMA1\/MYO5B signaling axis that inhibits breast cancer progression and osteolysis, disrupts tumor\u2013stromal interactions, and restores bone\u2013tumor homeostasis, thereby providing a potential therapeutic strategy to break the vicious cycle of bone metastasis in breast cancer.<\/jats:p>","DOI":"10.3390\/ijms27020777","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T10:13:51Z","timestamp":1768299231000},"page":"777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of Breast Cancer Bone Metastasis by LRP5-Overexpressing Osteocytes via the LIMA1\/MYO5B Signaling Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Yaning","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"},{"name":"Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing 100069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zicheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8330-942X","authenticated-orcid":false,"given":"Yu","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Metallic Biomaterials, Helmholtz-Zentrum Hereon, 21502 Geesthacht, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinshi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"},{"name":"Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing 100069, China"},{"name":"Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"},{"name":"Beijing Laboratory of Oral Health, Capital Medical University, Beijing 100069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengzhi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China"},{"name":"Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing 100069, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global Patterns and Trends in Breast Cancer Incidence and Mortality Across 185 Countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. 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