Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

Cell Death Dis. 2020 Jul 9;11(7):520. doi: 10.1038/s41419-020-2725-4.

Abstract

Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Disease Progression
  • Epithelial-Mesenchymal Transition
  • Female
  • HeLa Cells
  • Heterografts
  • Hippo Signaling Pathway
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis
  • Nuclear Proteins / metabolism*
  • Poly (ADP-Ribose) Polymerase-1 / biosynthesis
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Signal Transduction
  • Twist-Related Protein 1 / metabolism*

Substances

  • Nuclear Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Protein Serine-Threonine Kinases