Wang Chen, Li Jiehao, Ye Shuang, Zhang Yaxing, Li Ping, Wang Ling, Wang Ting-Huai
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.
J Cancer. 2018 Oct 1;9(20):3802-3811. doi: 10.7150/jca.29233. eCollection 2018.
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 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.
三阴性乳腺癌（TNBC）是最具恶性的乳腺癌类型，具有丰富的血管生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了与TNBC调节相关的多种细胞活动。然而，雌激素在TNBC中VEGF表达和血管生成中的作用仍不清楚。在本研究中，我们发现用17β-雌二醇（E2）处理可抑制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的条件培养基可抑制人脐静脉内皮细胞（HUVECs）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则显著逆转了E2和G-1对VEGF表达和管形成的抑制作用，表明GPER-1参与了E2诱导的TNBC细胞血管生成抑制。此外，E2抑制了MDA-MB-468异种移植肿瘤的生长和血管生成，并降低了VEGF、NF-κB/p65、STAT3和内皮标志物CD34的表达水平。我们的研究结果提供了重要证据，表明E2可通过激活GPER-1抑制TNBC中的VEGF表达和血管生成，为TNBC的肿瘤血管生成和药物干预靶点提供了更多见解。
