The role of P2X7 receptor in estrogen‐induced proliferation of breast cancer cells

Abstract

P2X7 is abnormally expressed in breast cancer cells. Activation of P2X7 receptor could either stimulate cell proliferation or induce apoptosis of tumor cells. Here, we examined whether estrogen could modulate the effect of P2X7 on MCF-7 cells by using MTT assay, QT-RT-PCR, western blotting analysis and siRNA transfection. The results indicated a significant correlation between ERa and P2X7 expression. 17β-estradiol (17β-E2) promoted proliferation of MCF-7 breast cells which could be blocked by the ERα antagonist MPP, but not by the ERβ antagonist PHTPP. The ERα agonist PPT but not the ERb agonist DPN could mimic estrogen effect. After depleting ERα by siRNA, 17β-E2 had no effect on cell proliferation, while application of ERβ siRNA lacked the similar effect. The P2X7 agonist BzATP significantly promoted the proliferation of MCF-7 cells which was blocked by the P2X receptor antagonist PPADS and P2X7 receptor antagonist BBG. The promotion effect of estrogen was blocked by PPADS and BBG. Application of estrogen upregulated P2X7 expression in both mRNA and protein levels, which was blocked by an ER antagonist ICI 182,780, MPP or application of ERα siRNA, while not by PHTPP. PPT but not DPN significantly increased P2X7 expression in MCF-7 cells. The GPR30 agonist, G-1 had no effect on either promotion of MCF-7 cells or P2X7 expression. Further, estrogen and PPT significantly increased expression of ERK1/2 and Akt expression in MCF-7 cells, which was blocked by ICI 182,780. The ERK1/2 antagonist, U0126 or the Akt antagonist, Ly294002 could block estrogen effect on P2X7 expression. These findings suggest that estrogen can promote breast cancer cell proliferation by upregulating P2X7 via ERa through ERK1/2 or Akt singnaling pathways.