{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T20:47:48Z","timestamp":1771015668723,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T00:00:00Z","timestamp":1619222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute (NCI) of the National Institutes of Health (NIH)","award":["R03CA18189"],"award-info":[{"award-number":["R03CA18189"]}]},{"name":"National Cancer Institute (NCI) of the National Institutes of Health (NIH)","award":["T32CA00923"],"award-info":[{"award-number":["T32CA00923"]}]},{"name":"National Cancer Institute (NCI) of the National Institutes of Health (NIH)","award":["P30CA023074"],"award-info":[{"award-number":["P30CA023074"]}]},{"name":"National Cancer Institute (NCI) of the National Institutes of Health (NIH)","award":["R01CA17492"],"award-info":[{"award-number":["R01CA17492"]}]},{"name":"METAvivor Foundation","award":["Translational Research Award"],"award-info":[{"award-number":["Translational Research Award"]}]},{"name":"Louise Foucar Marshall Foundation","award":["Dissertation Fellowship"],"award-info":[{"award-number":["Dissertation Fellowship"]}]},{"name":"ARCS Foundation, Phoenix Chapter","award":["ARCS Scholar Award"],"award-info":[{"award-number":["ARCS Scholar Award"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While tumoral Smad-mediated transforming growth factor \u03b2 (TGF\u03b2) signaling drives osteolytic estrogen receptor \u03b1-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGF\u03b2 signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E2)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGF\u03b2 receptors II and I, only cells with TGF\u03b2-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in &gt;90% of clinical BMETs, also tracked with osteolytic potential; TGF\u03b2 and E2 each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGF\u03b2 neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGF\u03b2 may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGF\u03b2 signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.<\/jats:p>","DOI":"10.3390\/ijms22094463","type":"journal-article","created":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T21:49:20Z","timestamp":1619300960000},"page":"4463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Role for TGF\u03b2 Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression"],"prefix":"10.3390","volume":"22","author":[{"given":"Julia N.","family":"Cheng","sequence":"first","affiliation":[{"name":"Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer B.","family":"Frye","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan A.","family":"Whitman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew G.","family":"Kunihiro","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritu","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet L.","family":"Funk","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,24]]},"reference":[{"key":"ref_1","first-page":"321","article-title":"Bone metastases: An overview","volume":"11","author":"Macedo","year":"2017","journal-title":"Oncol. 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