Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals
Triple-negative breast cancer (TNBC) are characterized by high vascularity and frequent metastasis.Here, we found that activation of G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 can significantly inhibit interleukin 6 (IL-6) and vascular endothelial growth factor A (VEGF-A).TNBC tissue microarrays from 100 TNBC patients revealed GPER is negatively associated with IL-6 levels and higher grade and stage.Activation of GPER or anti-IL-6 antibody can inhibit both in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and migration of TNBC cells.While recombinant IL-6 supplementary can significantly reverse the inhibitory effects of G-1, suggesting the essential role of IL-6 in G-1 induced suppression of angiogenesis and invasiveness of TNBC cells.G-1 treatment decreased the phosphorylation, nuclear localization,transcriptional activities of NF-κB and suppressed its binding with IL-6 promoter.BAY11-7028, the inhibitor of NF-κB, can mimic the effect of G-1 to suppression of IL-6 and VEGF-A.While over expression of p65 can attenuate the inhibitory effects of G-1 on IL-6 and VEGF expression.The suppression of IL-6 by G-1 can further inhibit HIF-1α and STAT3 signals in TNBC cells by inhibition their expression, phosphorylation and/or nuclear localization.Moreover, G-1 also inhibited the in vivo NF-κB/IL-6 signals and angiogenesis and metastasis of MDA-MB-231 xenograft tumors.In conclusion, our study demonstrated that activation of GPER can suppress migration and angiogenesis of TNBC via inhibition of NF-κB/IL-6 signals, therefore it maybe act as an important target for TNBC treatment.
GPER G-1 angiogenesis TNBC NF-κB
Zhuojia Chen Shuwei Liang Guanmin Jiang Yan Zhou Qiao Liu Qiao Su Weidong Wei Jun Du Hongsheng Wang
Sun Yat-sen University Cancer Center;State Key Laboratory of Oncology in South China;Collaborative I Department of Microbial and Biochemical Pharmacy,School of Pharmaceutical Sciences, Sun Yat-sen Univ Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine,Central South U Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080,
国内会议
广州
英文
130-142
2017-12-16（万方平台首次上网日期，不代表论文的发表时间）