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) is 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.
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Shuwei
S
Liang
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Zhuojia
Z
Chen
Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
Guanmin
G
Jiang
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Yan
Y
Zhou
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Qiao
Q
Liu
Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Qiao
Q
Su
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Weidong
W
Wei
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Jun
J
Du
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: whongsh@mail.sysu.edu.cn.
Hongsheng
H
Wang
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D000970:Antineoplastic Agents; D003517:Cyclopentanes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D016328:NF-kappa B; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; C109584:GPER1 protein, human; C497442:HIF1A protein, human; C508600:IL6 protein, human; C494086:STAT3 protein, human; C467484:VEGFA protein, human
Angiogenesis; G-1; GPER; NF-κB; TNBC