Objective:To investigate effects of activated G-protein coupled estrogen receptor(GPER) signaling pathway induced by estrogen on the production of interleukin-6 (IL-6) in ER-negative breast cancer cells. Methods:After treatment of SKBR-3 and MDA-MB-453 cells,the expression of IL-6 mRNA was measured by Real-time qPCR. The secretion of IL-6 in supernatant was detected by ELISA. The protein expression level of p-ERK and p-AKT was determined by Western blot. Results:17-β estradiol (E2) and GPER specific agonist (G1) significantly increased the mRNA expression of IL-6 in SKBR-3 and MDA-MB-453 cells,which could be blocked by GPER specific antagonist (G15). After treatment with E2 and G1,GPER/ERK and GPER/AKT signaling pathways were remarkably activated to promote the protein expression of p-ERK and p-AKT (P < 0.05). The relative protein expressions of p-AKT and p-ERK in the E2 and G1 treatment groups were (4.16 ± 0.65),(3.21 ± 0.45) and (2.87 ± 0.42),(2.64 ± 0.24) times than those of the control group,respectively,and the same results were obtained in MDA-MB-453 cells. Interestingly,these changes induced by E2 and G1 were significantly blocked by the MEK inhibitor U0126 rather than PI3K inhibitor Wortmannin (P < 0.05). Conclusion:Estrogen enhances the expression and secretion of IL-6 in ER(-) breast cancer cells,which may associates with the up-regulation of GPER/ERK signaling pathway,and the inflammatory microenvironment mediated by GPER may play an important role in the development of ER(-) breast cancer.