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Bone metastasis\u2010related complications including severe pain and pathological fractures affect patients' quality of life. Current treatment options including surgery, radiation, and bone\u2010targeted therapies (e.g., bisphosphonates) are costly or have serious adverse effects such as renal toxicity and osteonecrosis of the jaws. Therefore, a safe, inexpensive, and efficacious agent for prevention of breast cancer bone metastasis is urgently needed. Our previously published RNA sequencing analysis revealed that many genes implicated in bone remodeling and breast cancer bone metastasis were significantly downregulated by treatment with withaferin A (WA), which is a promising cancer chemopreventive agent derived from a medicinal plant (<jats:italic>Withania somnifera<\/jats:italic>). The present study investigated whether WA inhibits breast cancer induction of osteoclast differentiation. At plasma achievable doses, WA treatment inhibited osteoclast differentiation (osteoclastogenesis) induced by three different subtypes of breast cancer cells (MCF\u20107, SK\u2010BR\u20103, and MDA\u2010MB\u2010231). WA and the root extract of <jats:italic>W. somnifera<\/jats:italic> were equally effective for inhibition of breast cancer induction of osteoclast differentiation. This inhibition was accompanied by suppression of <jats:italic>interleukin<\/jats:italic> (<jats:italic>IL<\/jats:italic>)\u2010<jats:italic>6, IL\u20108<\/jats:italic>, and <jats:italic>receptor activator of nuclear factor\u2010\u03baB ligand<\/jats:italic>, which are pivotal osteoclastogenic cytokines. The expression of runt\u2010related transcription factor 2, nuclear factor\u2010\u03baB, and SOX9 transcription factors, which positively regulate osteoclastogenesis, was decreased in WA\u2010treated breast cancer cells as revealed by confocal microscopy and\/or immunoblotting. Taken together, these data suggest that WA could be a promising agent for prevention of breast cancer\u2010induced bone metastasis.<\/jats:p>","DOI":"10.1002\/mc.23545","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T13:45:56Z","timestamp":1681739156000},"page":"1051-1061","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Withaferin A inhibits breast cancer\u2010induced osteoclast differentiation"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3197-4575","authenticated-orcid":false,"given":"Eun\u2010Ryeong","family":"Hahm","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Chemical Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u2010Hyeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Chemical Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3733-144X","authenticated-orcid":false,"given":"Shivendra V.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Chemical Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA"},{"name":"University of Pittsburgh School of Medicine UPMC Hillman Cancer Center  Pittsburgh Pennsylvania 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