Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals.

Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE

Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.

Neovascularization, Pathologic*; Antineoplastic Agents/*pharmacology ; Cell Movement/*drug effects ; Cyclopentanes/*pharmacology ; Interleukin-6/*metabolism ; NF-kappa B/*metabolism ; Quinolines/*pharmacology ; Receptors, G-Protein-Coupled/*agonists ; Triple Negative Breast Neoplasms/*drug therapy; Animals ; Antibodies/pharmacology ; Binding Sites ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Interleukin-6/antagonists & inhibitors ; Interleukin-6/genetics ; Mice, Nude ; Middle Aged ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/genetics ; Neoplasm Invasiveness ; Neovascularization, Physiologic/drug effects ; Phosphorylation ; Promoter Regions, Genetic ; Receptors, Estrogen/metabolism ; Receptors, G-Protein-Coupled/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Time Factors ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Tumor Burden/drug effects ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays

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.
(Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Erratum in: Cancer Lett. 2018 Feb 1;414:310. doi: 10.1016/j.canlet.2017.10.025. (PMID: 29097156)
Erratum in: Cancer Lett. 2021 Feb 1;498:251-252. doi: 10.1016/j.canlet.2020.07.036. (PMID: 32859427)

Keywords: Angiogenesis; G-1; GPER; NF-κB; TNBC

0 (1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone)
0 (Antibodies)
0 (Antineoplastic Agents)
0 (Cyclopentanes)
0 (GPER1 protein, human)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (IL6 protein, human)
0 (Interleukin-6)
0 (NF-kappa B)
0 (Quinolines)
0 (Receptors, Estrogen)
0 (Receptors, G-Protein-Coupled)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
0 (VEGFA protein, human)
0 (Vascular Endothelial Growth Factor A)

Date Created: 20161113 Date Completed: 20170808 Latest Revision: 20190816

20250114

10.1016/j.canlet.2016.11.003

27836733