PTGER3 knockdown inhibits the vulnerability of triple‐negative breast cancer to ferroptosis

Prostaglandin E receptor 3 (PTGER3) is involved in a variety of biological processes in the human body and is closely associated with the development and progression of a variety of cancer types. However, the role of PTGER3 in triple‐negative breast cancer (TNBC) remains unclear. In the present study, low PTGER3 expression was found to be associated with poor prognosis in TNBC patients. PTGER3 plays a crucial role in regulating TNBC cell invasion, migration, and proliferation. Upregulation of PTGER3 weakens the epithelial–mesenchymal phenotype in TNBC and promotes ferroptosis both in vitro and in vivo by repressing glutathione peroxidase 4 (GPX4) expression. On the other hand, downregulation of PTGER3 inhibits ferroptosis by increasing GPX4 expression and activating the PI3K‐AKT pathway. Upregulation of PTGER3 also enhances the sensitivity of TNBC cells to paclitaxel. Overall, this study has elucidated critical pathways in which low PTGER3 expression protects TNBC cells from undergoing ferroptosis, thereby promoting its progression. PTGER3 may thus serve as a novel and promising biomarker and therapeutic target for TNBC. PTGER3 overexpression can inhibit GPX4 expression, possibly via cAMP pathway inhibition through membranous PTGER3 expression and direct transcriptional inhibition through nuclear PTGER3 expression. Loss of PTGER3 expression leads to triple‐negative breast cancer (TNBC) cells ferroptosis resistance through loss of inhibitory cAMP pathway function, increasing GPX4/GSH activity, and activation of the PI3K‐AKT pathway.