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.

Liang S ，Chen Z ，Jiang G ，Zhou Y ，Liu Q ，Su Q ，Wei W ，Du J ，Wang H ... -  《-》

Activation of GPER suppresses epithelial mesenchymal transition of triple negative breast cancer cells via NF-κB signals.

The targeted therapy for triple-negative breast cancer (TNBC) is a great challenge due to our poor understanding on its molecular etiology. In the present study, our clinical data showed that the expression of G-protein coupled estrogen receptor (GPER) is negatively associated with lymph node metastasis, high-grade tumor and fibronectin (FN) expression while positively associated with the favorable outcome in 135 TNBC patients. In our experimental studies, both the in vitro migration and invasion of TNBC cells were inhibited by GPER specific agonist G-1, through the suppression of the epithelial mesenchymal transition (EMT). The G-1 treatment also reduced the phosphorylation, nuclear localization, and transcriptional activities of NF-κB. While over expression of NF-κB attenuated the action of G-1 in suppressing EMT. Our data further illustrated that the phosphorylation of GSK-3β by PI3K/Akt and ERK1/2 mediated, at least partially, the inhibitory effect of G-1 on NF-κB activities. It was further confirmed in a study of MDA-MB-231 tumor xenografts in nude mice. The data showed that G-1 inhibited the in vivo growth and invasive potential of TNBC via suppression of EMT. Our present study demonstrated that an activation of GPER pathway elicits tumor suppressive actions on TNBC, and supports the use of G-1 therapeutics for TNBC metastasis.

Chen ZJ ，Wei W ，Jiang GM ，Liu H ，Wei WD ，Yang X ，Wu YM ，Liu H ，Wong CK ，Du J ，Wang HS ... -  《-》

Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals.

Zhu G ，Huang Y ，Wu C ，Wei D ，Shi Y ... -  《-》

Interaction of EZH2 and P65 is involved in the arsenic trioxide-induced anti-angiogenesis in human triple-negative breast cancer cells.

Jiang F ，Li Y ，Si L ，Zhang Z ，Li Z ... -  《-》

Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin.

Wu YM ，Chen ZJ ，Liu H ，Wei WD ，Lu LL ，Yang XL ，Liang WT ，Liu T ，Liu HL ，Du J ，Wang HS ... -  《Oncotarget》