Piperlongumine suppresses YAP-ET-1-CXCL2 signaling to modulates aggressiveness of triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is characterized by highly aggressive and metastatic properties, and appropriate molecular targets and therapeutics for effective treatment remain limited. In the present study, by using RNA sequencing (RNA-Seq) analysis of upregulated genes expression in metastatic breast tumor cells, we identified that the Yes-associated protein (YAP)- endothelin (ET)-1 signaling axis were concomitantly elevated in metastatic breast tumor tissues and their overexpression conferred poor survival outcomes, particular in patients with TNBC. Moreover, we identified that piperlongumine (PL), a naturally occurring small molecule derived from long pepper, exhibits potent antitumor activities in TNBC cells. PL effectively suppressed cell proliferation, promoted apoptosis, and inhibited tumor migration and invasion. Furthermore, PL activates Hippo signaling which was accompanied by downregulation of YAP level. Consequently, PL suppressed YAP signaling to further downregulate ET-1 expression. Additionally, ET-1 elevation was identified to be associated with cancer-associated fibroblast (CAF) and C-X-C motif chemokine ligand 2 (CXCL2) signature, while treatment with PL significantly downregulated CXCL2 expression and consequently decreased CAF activation. Finally, PL treatment significantly inhibited in vivo tumor growth and suppressed CAF infiltration in the tumor microenvironment. Together, these findings demonstrated that PL might be a promising chemotherapeutic agent to efficiently target YAP-ET-1-CXCL2 signaling and thus has therapeutic potential for TNBC patients.