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obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF\/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF\/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.<\/jats:p>","DOI":"10.3390\/cancers16213630","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T07:04:04Z","timestamp":1730099044000},"page":"3630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Significance of LIF\/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Lois","family":"Randolph","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaitri","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alondra Lee","family":"Rodriguez Sanchez","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uday P.","family":"Pratap","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Gopalam","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidong","family":"Chen","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Lai","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindu","family":"Santhamma","sequence":"additional","affiliation":[{"name":"Evestra, Inc., San Antonio, TX 78245, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward R.","family":"Kost","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hareesh B.","family":"Nair","sequence":"additional","affiliation":[{"name":"Evestra, Inc., San Antonio, TX 78245, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2849-4076","authenticated-orcid":false,"given":"Ratna K.","family":"Vadlamudi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Audie L. 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