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TIMP-1 depletion reverses chemoresistance by blocking AKT activation, while exogenous TIMP-1 restores resistance; CD63 dependence is demonstrated at the membrane binding level.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/tissue-inhibitor-of-metalloproteinases-1-overexpression-mediates-chemoresistance-in-triple-negative-breast-cancer-cells/384899/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/tissue-inhibitor-of-metalloproteinases-1-overexpression-mediates-chemoresistance-in-triple-negative-breast-cancer-cells/384899.png","ImageObject",300,407,{"name":42,"@type":43},"Sophia Brooks","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-04","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the role of TIMP-1 in triple-negative breast cancer chemoresistance?","Question",{"text":63,"@type":64},"The study links higher TIMP-1 levels to TNBC chemoresistance. TIMP-1 knock-down reverses resistance, while TIMP-1 addition restores resistance.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How do cisplatin- and doxorubicin-resistant TNBC models differ regarding TIMP-1?",{"text":68,"@type":64},"Mesenchymal-like TNBC cells express TIMP-1, and TIMP-1 levels increase further in cells generated resistant to cisplatin and doxorubicin.",{"name":70,"@type":61,"acceptedAnswer":71},"Why is CD63 important for TIMP-1-mediated chemoresistance?",{"text":72,"@type":64},"Released TIMP-1 reassociates with the plasma membrane by binding to CD63. 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Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells. Cells 2023, 12, 1809. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12131809  \nAcademic Editor: Dipali Sharma  \nReceived: 7 June 2023  \nRevised: 27 June 2023  \nAccepted: 6 July 2023  \nPublished: 7 July 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), 80131 Naples, Italy; [l.agnello@ieos.cnr.it](l.agnello@ieos.cnr.it) (L.A.); [a.dargenio@ieos.cnr.it](a.dargenio@ieos.cnr.it) (A.d.); [alessandracaliendo9@gmail.com](alessandracaliendo9@gmail.com) (A.C.); [r.nilo@ieos.cnr.it](r.nilo@ieos.cnr.it) (R.N.); [mfedele@unina.it](mfedele@unina.it) (M.F.); [s.camorani@ieos.cnr.it](s.camorani@ieos.cnr.it) (S.C.)  \n2 Institute of Biostructures and Bioimaging, National Research Council (CNR), 80145 Naples, Italy; [antonella.zannetti@ibb.cnr.it](antonella.zannetti@ibb.cnr.it)  \n* Correspondence: cerchia@unina.it or [laura.cerchia@ieos.cnr.it](laura.cerchia@ieos.cnr.it)[ ](laura.cerchia@ieos.cnr.it)† These authors contributed equally to this work.  \nAbstract: 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.  \nKeywords: chemoresistance; triple-negative breast cancer; tumor microenvironment; tissue inhibitor of metalloproteinases-1; CD63 cell receptor  \n1. Introduction  \nTriple-negative breast cancer (TNBC), representing approximately 15–20% of all breast cancer (BC) diagnosed worldwide, is defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) [1,2] . TNBC clinical features include high invasiveness, metastatic potential and rate of relapse [3] . Unfortunately, despite having higher","cbCaibERg721Qa5G","https://ap.wps.com/l/cbCaibERg721Qa5G","pdf",6965274,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"What is the role of TIMP-1 in triple-negative breast cancer chemoresistance?\",\"answer\":\"The study links higher TIMP-1 levels to TNBC chemoresistance. TIMP-1 knock-down reverses resistance, while TIMP-1 addition restores resistance.\"},{\"question\":\"How do cisplatin- and doxorubicin-resistant TNBC models differ regarding TIMP-1?\",\"answer\":\"Mesenchymal-like TNBC cells express TIMP-1, and TIMP-1 levels increase further in cells generated resistant to cisplatin and doxorubicin.\"},{\"question\":\"Why is CD63 important for TIMP-1-mediated chemoresistance?\",\"answer\":\"Released TIMP-1 reassociates with the plasma membrane by binding to CD63. When CD63 expression is absent, TIMP-1-mediated chemoresistance is blocked.\"}]","Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells | PDF",1790265712]