Protease activated receptor-1 regulates mixed lineage kinase-3 to drive triple-negative breast cancer tumorigenesis.

Autor: Srivastava P; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Jha S; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Singh SK; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Vyas H; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Sethupathi P; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Nair RS; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Ramachandran K; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA., Rana B; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA; Research Unit, Jesse Brown VA Medical Center, Chicago, IL, 60612, USA., Kumar S; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA. Electronic address: ksandeep@uic.edu., Rana A; Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA; Research Unit, Jesse Brown VA Medical Center, Chicago, IL, 60612, USA. Electronic address: arana@uic.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Oct 28; Vol. 603, pp. 217200. Date of Electronic Publication: 2024 Aug 31.
DOI: 10.1016/j.canlet.2024.217200
Abstrakt: Triple-negative breast cancer (TNBC) is difficult to treat breast cancer subtype due to lack or insignificant expressions of targetable estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Therefore, finding a targetable protein or signaling pathway in TNBC would impact patient care. Here, we report that a member of the Mixed Lineage Kinase (MLK) family, MLK3, is an effector of G-protein-coupled protease-activated receptors 1 (PAR1) and targeting MLK3 by a small-molecule inhibitor prevented PAR1-mediated TNBC tumorigenesis. In silico and immunohistochemistry analysis of human breast tumors showed overexpression of PAR1 and MLK3 in TNBC tumors. Treating α-thrombin and PAR1 agonist increased MLK3 and JNK activities and induced cell migration in TNBC cells. The PAR1 positive/high (PAR1 +/hi ) population of TNBC cells showed aggressive tumor phenotype with increased MLK3 signaling. Moreover, combined inhibition of the PAR1 and MLK3 mitigated the TNBC tumor burden in preclinical TNBC models. Our data suggests that activation of the PAR1-MLK3 axis promotes TNBC tumorigenesis. Therefore, combinatorial therapy targeting MLK3 and PAR1 could effectively reduce TNBC tumor burden.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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