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

Piush Srivastava1, Saket Jha1, Sunil Kumar Singh1

  • 1Department of Surgery, Division of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Cancer Letters
|September 2, 2024
PubMed

Insights

Targeting the PAR1-MLK3 pathway shows promise for treating triple-negative breast cancer (TNBC). Inhibiting MLK3 and PAR1 effectively reduced TNBC tumor growth in preclinical models, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Triple-negative breast cancer (TNBC) lacks specific molecular targets like ER and HER2, making treatment challenging.
  • Identifying novel therapeutic targets is crucial for improving patient outcomes in TNBC.

Purpose of the Study:

  • To investigate the role of Mixed Lineage Kinase 3 (MLK3) as a therapeutic target in triple-negative breast cancer.
  • To explore the relationship between G-protein-coupled protease-activated receptors 1 (PAR1) and MLK3 signaling in TNBC tumorigenesis.

Main Methods:

  • In silico and immunohistochemistry analysis of human breast tumors.
  • Functional assays involving TNBC cell lines treated with thrombin and PAR1 agonists.
  • Preclinical studies using TNBC models to evaluate combined PAR1 and MLK3 inhibition.

Main Results:

  • Overexpression of PAR1 and MLK3 was observed in TNBC tumors.
  • PAR1 activation led to increased MLK3 and JNK activity and enhanced cell migration in TNBC cells.
  • Combined inhibition of PAR1 and MLK3 significantly reduced TNBC tumor burden in preclinical models.

Conclusions:

  • The PAR1-MLK3 signaling axis promotes TNBC tumorigenesis.
  • Targeting MLK3, particularly in combination with PAR1, represents a potential therapeutic strategy for TNBC.
Keywords:
JNKMLK3MetastasisPAR1TNBCThrombin

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