{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:23:14Z","timestamp":1790868194959,"version":"4.1.0"},"reference-count":84,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T00:00:00Z","timestamp":1688688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione AIRC per la Ricerca sul Cancro","award":["23052"],"award-info":[{"award-number":["23052"]}]},{"name":"Fondazione AIRC per la Ricerca sul Cancro","award":["26742"],"award-info":[{"award-number":["26742"]}]},{"name":"AIRC Fellowship for Italy","award":["23052"],"award-info":[{"award-number":["23052"]}]},{"name":"AIRC Fellowship for Italy","award":["26742"],"award-info":[{"award-number":["26742"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop drug-resistant and metastatic tumors. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a secreted protein with a tumor suppressor function due to its anti-proteolytic activity. Nevertheless, evidence indicates that TIMP-1 binds to the CD63 receptor and activates noncanonical oncogenic signaling in several cancers, but its role in mediating TNBC chemoresistance is still largely unexplored. Here, we show that mesenchymal-like TNBC cells express TIMP-1, whose levels are further increased in cells generated to be resistant to cisplatin (Cis-Pt-R) and doxorubicin (Dox-R). Moreover, public dataset analyses indicate that high TIMP-1 levels are associated with a worse prognosis in TNBC subjected to chemotherapy. Knock-down of TIMP-1 in both Cis-Pt-R and Dox-R cells reverses their resistance by inhibiting AKT activation. Consistently, TNBC cells exposed to recombinant TIMP-1 or TIMP-1-enriched media from chemoresistant cells, acquire resistance to both cisplatin and doxorubicin. Importantly, released TIMP-1 reassociates with plasma membrane by binding to CD63 and, in the absence of CD63 expression, TIMP-1-mediated chemoresistance is blocked. Thus, our results identify TIMP-1 as a new biomarker of TNBC chemoresistance and lay the groundwork for evaluating whether blockade of TIMP-1 signal is a viable treatment strategy.<\/jats:p>","DOI":"10.3390\/cells12131809","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:45:37Z","timestamp":1688949937000},"page":"1809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-1987","authenticated-orcid":false,"given":"Lisa","family":"Agnello","sequence":"first","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annachiara","family":"d\u2019Argenio","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2506-513X","authenticated-orcid":false,"given":"Alessandra","family":"Caliendo","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Nilo","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6753-3659","authenticated-orcid":false,"given":"Antonella","family":"Zannetti","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council (CNR), 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-1312","authenticated-orcid":false,"given":"Monica","family":"Fedele","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1144-0485","authenticated-orcid":false,"given":"Simona","family":"Camorani","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-7932","authenticated-orcid":false,"given":"Laura","family":"Cerchia","sequence":"additional","affiliation":[{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. Salvatore\u201d, National Research Council (CNR), 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1056\/NEJMra1001389","article-title":"Triple-negative breast cancer","volume":"363","author":"Foulkes","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1146\/annurev-pathol-042420-093238","article-title":"Pathogenesis of Triple-Negative Breast Cancer","volume":"17","author":"Derakhshan","year":"2022","journal-title":"Annu. Rev. 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