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07 07, 2023;12 (13):

Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells.

Lisa Agnello, Annachiara d'Argenio, Alessandra Caliendo, Roberto Nilo, Antonella Zannetti, Monica Fedele, Simona Camorani, Laura Cerchia
Author Information
  1. Lisa Agnello: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy. ORCID
  2. Annachiara d'Argenio: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy.
  3. Alessandra Caliendo: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy. ORCID
  4. Roberto Nilo: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy.
  5. Antonella Zannetti: Institute of Biostructures and Bioimaging, National Research Council (CNR), 80145 Naples, Italy. ORCID
  6. Monica Fedele: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy. ORCID
  7. Simona Camorani: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy. ORCID
  8. Laura Cerchia: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), 80131 Naples, Italy. ORCID
PMID: 37443843 DOI: 10.3390/cells12131809

Abstract

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.

Keywords

CD63 cell receptor chemoresistance tissue inhibitor of metalloproteinases-1 triple-negative breast cancer tumor microenvironment

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Grants

  1. 23052/Fondazione Associazione Italiana per la Ricerca sul Cancro

MeSH Term

Humans
Triple Negative Breast Neoplasms
Tissue Inhibitor of Metalloproteinase-1
Cisplatin
Drug Resistance, Neoplasm
Doxorubicin

Chemicals

Tissue Inhibitor of Metalloproteinase-1
Cisplatin
Doxorubicin
Journal Article Research Support, Non-U.S. Gov't

Word Cloud

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