Oestrogen Inhibits VEGF Expression And Angiogenesis In Triple-Negative Breast Cancer By Activating GPER-1.
Oestrogen Inhibits VEGF Expression And Angiogenesis In Triple-Negative Breast Cancer By Activating GPER-1.
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雌激素通过激活 GPER-1 抑制三阴性乳腺癌中 VEGF 表达和血管生成
DOI：
10.7150/jca.29233
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发表时间：
2018
影响因子：
3.9
通讯作者：
Wang TH
中科院分区：
文献类型：
--
作者：
Wang C;Li J;Ye S;Zhang Y;Li P;Wang L;Wang TH
三阴性乳腺癌（TNBC）是最恶性的乳腺癌类型，具有丰富的血管形成和高血管内皮生长因子（VEGF）表达。性类固醇激素雌激素参与与TNBC调节相关的几种细胞活动。然而，雌激素在TNBC中VEGF表达和血管生成中的作用仍不清楚。在这项研究中，我们发现用17β-雌二醇（E2）处理抑制TNBC细胞系MDA-MB-468和MDA-MB-436中VEGF mRNA和蛋白的表达。为了进一步阐述E2调节血管生成的现象，我们表明，用E2处理的TNBC细胞系MDA-MB-468的条件培养基抑制人脐静脉内皮细胞（HUVEC）的管形成能力。此外，G蛋白偶联雌激素受体-1（GPER-1）特异性激动剂G-1具有与E2相似的功能。而GPER-1的选择性拮抗剂G-15可显著逆转E2和G-1对VEGF表达和小管形成的抑制作用，提示GPER-1参与E2诱导的TNBC细胞血管生成抑制。此外，E2抑制体内肿瘤生长和血管生成，并降低MDA-MB-468异种移植瘤中VEGF、NF-κB/p65、STAT 3和内皮标记物CD 34的表达水平。我们的研究结果提供了重要的证据，即E2可以通过激活GPER-1来抑制TNBC中的VEGF表达和血管生成，从而为TNBC中的肿瘤血管生成和药物干预靶点提供了额外的见解。
Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer with ample vascularisation and high vascular endothelial growth factor (VEGF) expression. The sex steroid hormone oestrogen is involved in several cellular activities associated with TNBC regulation. However, the role of oestrogen in VEGF expression and angiogenesis in TNBC remains unclear. In this study, we found that treatment with 17β-oestradiol (E2) inhibited VEGF mRNA and protein expression in the TNBC cell lines MDA-MB-468 and MDA-MB-436. To further elaborate on the phenomenon of E2-regulated angiogenesis, we showed that conditioned medium from the TNBC cell line MDA-MB-468 treated with E2 inhibits the tube formation ability of human umbilical vein endothelial cells (HUVECs). Additionally, the G-protein-coupled oestrogen receptor-1 (GPER-1)-specific agonist G-1 has a function similar to that of E2. While G-15, the selective antagonist of GPER-1, notably reversed the inhibitory effects of E2 and G-1 on VEGF expression and tube formation, suggesting that GPER-1 is involved in the E2-induced angiogenesis suppression in TNBC cells. Moreover, E2 inhibited in vivo tumour growth and angiogenesis and reduced the expression levels of VEGF, NF-κB/p65, STAT3, and the endothelial marker CD34 in MDA-MB-468 xenograft tumours. Our findings provide important evidence that E2 can inhibit VEGF expression and angiogenesis in TNBC by activating GPER-1, offering additional insight into tumour angiogenesis and targets for drug intervention in TNBC.