{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:41:31Z","timestamp":1790361691671,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tunisian Ministry of Higher Education and Scientific Research","award":["13G0819"],"award-info":[{"award-number":["13G0819"]}]},{"name":"Institut National du Cancer","award":["PLBIO INCa 2018-1-PLBIO-05"],"award-info":[{"award-number":["PLBIO INCa 2018-1-PLBIO-05"]}]},{"name":"Association de Recherche contre le Cancer","award":["20171206570"],"award-info":[{"award-number":["20171206570"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: Obesity-associated hyperleptinemia has been linked to breast cancer (BC) progression via mechanisms that remain incompletely understood. This study explores the role of leptin and its receptor (LEPR) in facilitating BC cell proliferation, migration, epithelial\u2013mesenchymal transition (EMT), and STAT3 signaling pathway activation. Methods: We analyzed gene expression and survival data from TCGA BRCA dataset. MCF-7 and MDA-MB-231 BC cells were exposed to leptin at 10 ng\/mL (lean-associated levels) and 100 ng\/mL (elevated levels linked to obesity). MTT assays, colony formation tests, wound-healing and tumor spheroid dissemination experiments evaluated cell proliferation and migration. Immunofluorescence and Western blot analysis assessed changes in EMT markers and cytoskeletal alterations, while Western blotting and qPCR assessed STAT3 and NCOA1 expression and activation levels. Results: Elevated LEPR expression was linked with unfavorable prognosis in BC patients. Higher doses of leptin (100 ng\/mL) significantly enhanced cellular proliferation rates and migratory capabilities, in both cell lines, and promoted EMT characteristics marked by downregulated E-cadherin and cytoskeleton structural changes. Whereas heightened JAK2\/STAT3 signaling correlated with elevated leptin dosages, STAT3 inhibition using AG490 reversed leptin-induced migration while reinstating E-cadherin levels to baseline. Furthermore, leptin upregulated NCOA1, an essential STAT3 coactivator, facilitating increased expression of Cyclin D1 and VEGF target genes. Clinical positive relationships were seen between LEP\/LEPR expressions and NCOA1 levels and between NCOA1 and various gene signatures related to STAT3\/P-STAT3 within BC specimens. Conclusions: Obesity-associated hyperleptinemia enhances aggressiveness in BC through a mechanism involving LEPR-mediated activation pathways encompassing NCOA1\/STAT3, which drive proliferation, migration, and EMT. This assigns a potential therapeutic utility for obesity-related advancements found within BC pathology.<\/jats:p>","DOI":"10.3390\/medsci14010032","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T09:01:29Z","timestamp":1767862889000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Leptin Drives Breast Cancer Aggressiveness Acting Through the Activation of the NCOA1\/STAT3 Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-8597","authenticated-orcid":false,"given":"Khouloud","family":"Ayed","sequence":"first","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Gorrab","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hichem","family":"Bouguerra","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-3775","authenticated-orcid":false,"given":"Rym","family":"Akrout","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0079-5061","authenticated-orcid":false,"given":"Sami","family":"Zekri","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis 1007, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wassim Y.","family":"Almawi","sequence":"additional","affiliation":[{"name":"Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"},{"name":"Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahma","family":"Boughriba","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3534-8237","authenticated-orcid":false,"given":"Khalil","family":"Choukri","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8430-0072","authenticated-orcid":false,"given":"Dhouha","family":"Bacha","sequence":"additional","affiliation":[{"name":"Service d\u2019Anatomie Pathologique, H\u00f4pital Mongi Slim, La Marsa 2046, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Pagano","sequence":"additional","affiliation":[{"name":"Equipe 9 Cytosquelette et Neurophysiopathologie, Facult\u00e9 Pharmacie site Timone, UMR7051 Institut de Neuro Physiopathologie (INP), 27 Bd Jean-Moulin, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1626-7098","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Louet","sequence":"additional","affiliation":[{"name":"Adipo-Cible Research Study Group, Mediterranean Center of Molecular Medicine, Department of Molecular and Cellular Biology, C\u00f4te d\u2019Azur University Inserm, 06204 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6509-4210","authenticated-orcid":false,"given":"Herv\u00e9","family":"Kovacic","sequence":"additional","affiliation":[{"name":"Equipe 9 Cytosquelette et Neurophysiopathologie, Facult\u00e9 Pharmacie site Timone, UMR7051 Institut de Neuro Physiopathologie (INP), 27 Bd Jean-Moulin, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-063X","authenticated-orcid":false,"given":"Mounia","family":"Tannour-Louet","sequence":"additional","affiliation":[{"name":"Adipo-Cible Research Study Group, Mediterranean Center of Molecular Medicine, Department of Molecular and Cellular Biology, C\u00f4te d\u2019Azur University Inserm, 06204 Nice, France"},{"name":"CNRS, Inserm, Institute of Molecular and Cellular Pharmacology, C\u00f4te d\u2019Azur University, 06560 Valbonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8507-0451","authenticated-orcid":false,"given":"Asma","family":"Gati","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Immunology, and Human Pathologies, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"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 A Cancer J. 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