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.
Highlights
Protease-activated receptor 1 (PAR1) expression is upregulated in highly invasive breast cancer
We noticed that PAR1 expression was significantly higher in highly invasive breast cancer cells than in low invasive breast cancer cell lines (Fig. 1a and Supplementary Fig. 1a)
In this study, we report that high PAR expression is correlated with invasive breast cancer, and PAR1 enhances the tumorigenic and metastatic capacity of breast cancer cells by attenuating the Hippo pathway and activating epithelial-mesenchymal transition (EMT) program
Summary
Despite extensive progress in understanding mechanisms of breast cancer progression and developing therapeutic strategies, ~90% of breast cancer mortality is due to recurrent and metastasis[1]. The increased motility and invasive capabilities of metastatic tumor cells are associated with the epithelial-mesenchymal transition (EMT), a phenotypic conversion by which cells lose apico-basal polarity and acquire highly motile mesenchymal properties[2,3,4,5,6]. EMT confers tumor cells with cancer stem cell (CSC) features, promoting tumor progression and metastasis[7]. Increasing studies have shown that some highly. The Hippo pathway is a key player in several carcinogenesis processes, including cell proliferation, apoptosis, and stem cell maintenance[12,13]. The core upstream components of the Hippo pathway such as MST1/2, SAV1, and
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