Blocking or knockdown of P2X7 receptor inhibits invasion and migration of mouse breast cancer cells via PI3K/Akt/GSK-3β pathways and EMT.

P2X7 receptor (P2X7R), an ATP-activated ion channel, is essential for the invasion, migration, and proliferation of tumor cells. Elevated P2X7R expression has been observed in breast cancer cells and adjacent tissues, yet its precise role in breast cancer progression remains incompletely understood. This study investigates the impact of P2X7R activation, inhibition, and knockdown (via P2X7R-shRNA) on breast cancer cell (E0771 and 4T1) migration, invasion, epithelial-mesenchymal transition (EMT), and underlying molecular mechanisms through comprehensive cellular and animal experiments. Our results demonstrate functional P2X7R expression in breast cancer cells, with BzATP enhancing and P2X7R-shRNA reducing its expression. P2X7R activation promotes EMT-mediated invasion and migration in breast cancer cells, whereas P2X7R antagonists or P2X7R-shRNA counteract these effects. Furthermore, P2X7R activation stimulates the PI3K/Akt/GSK-3β signaling pathway, thereby facilitating breast cancer progression. Consistent with in vitro findings, in vivo models with P2X7R-knockdown breast cancer cells showed suppressed tumor growth and metastasis, correlating with EMT and PI3K/Akt/GSK-3β pathway modulation. Additionally, host P2X7R mouse models revealed that host P2X7R deficiency inhibits tumor growth and metastasis, potentially through similar pathways. These findings suggest that targeting P2X7R may offer novel therapeutic strategies and experimental foundations for breast cancer treatment.