Thrombin-PAR1 signaling regulates Topoisomerase 1 activity to bridge inflammation and breast cancer progression.

Deregulation of coagulation proteases can lead to a spectrum of hemostatic abnormalities, ranging from subtle subclinical to life-threatening coagulopathies. Additionally, coagulation factors play critical roles in many abnormalities beyond thrombosis, extending to hyperactive inflammatory responses and promoting tumorigenesis. Triple-negative breast cancers (TNBCs) are marked by a pro-thrombotic and highly inflammatory tumor microenvironment that fuels progression and therapeutic resistance, yet the molecular crosstalk linking coagulation signaling to inflammatory transcription remains incompletely understood. Here, we identify DNA topoisomerase I (Top1) as a critical downstream effector of thrombin-PAR1 driven inflammatory reprogramming in breast cancer cells. Thrombin enhances Top1 activity without altering its expression, amplifying NF-κB dependent cytokine production. Mechanistically, this response is governed by suppression of the tumor suppressor Par-4, which resides at the epicentre of this signaling axis and negatively regulates both Top1 and NF-κB. PAR1 activation enforces Par-4 loss through coordinated epigenetic silencing and phosphorylation-dependent cytoplasmic inactivation, thereby relieving transcriptional constraints and sustaining pro-tumorigenic inflammation. Importantly, targeting PAR1 markedly sensitizes TNBC tumors to the Top1 inhibitor irinotecan, highlighting a therapeutically actionable vulnerability. These findings reveal a previously unappreciated convergence of coagulation, epigenetic control, transcriptional activation and DNA topology control in breast cancer-suggesting the possibility of repurposing FDA-approved oral anticoagulants as an effective combinatorial therapy along with Top1 poisons in treating TNBCs.