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.

乳腺癌被认为是全世界女性中最普遍的癌症，转移是死亡的主要原因。蛋白酶激活受体1（PAR1）是GPCR家族成员，参与癌细胞的侵袭和转移过程。但是，PAR1在乳腺癌中的功能和潜在机制仍不清楚。在这项研究中，我们发现PAR1在高浸润性乳腺癌细胞中高表达，并预测ER阴性和高等级乳腺癌患者的预后不良。从机制上讲，Twist在转录上诱导PAR1表达，导致抑制Hippo途径和激活YAP / TAZ。抑制PAR1可抑制YAP / TAZ诱导的上皮-间质转化（EMT），侵袭，迁移，癌症干细胞（CSC）样特性，体外和体内乳腺癌细胞的肿瘤生长和转移。这些发现表明，PAR1是Twist的直接转录靶标，可以通过控制Hippo途径来促进EMT，致瘤性和转移。这可能会导致潜在的治疗浸润性乳腺癌的治疗目标。