State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
Clinical Laboratory, The 305 Hospital of The People's Liberation Army, 100017, Beijing, People's Republic of China.
Cell Death Dis. 2018 Jul 3;9(7):744. doi: 10.1038/s41419-018-0790-8.
Forkhead box P3 (FOXP3), an X-linked tumor suppressor gene, plays an important role in breast cancer. However, the biological functions of FOXP3 in breast cancer angiogenesis remain unclear. Here we found that the clinical expression of nuclear FOXP3 was inversely correlated with breast cancer angiogenesis. Moreover, the animal study demonstrated that FOXP3 significantly reduced the microvascular density of MDA-MB-231 tumors transplanted in mice. The cytological experiments showed that the supernatant from FOXP3-overexpressing cells exhibited a diminished ability to stimulate tube formation and sprouting in HUVECs in vitro. In addition, expression of vascular endothelial growth factor (VEGF) was downregulated by FOXP3 in breast cancer cell lines. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that FOXP3 can directly interact with the VEGF promoter via specific forkhead-binding motifs to suppress its transcription. Importantly, the inhibitory effects of FOXP3 in the supernatant on tube formation and sprouting in HUVECs could be reversed by adding VEGF in vitro. Nuclear FOXP3 expression was inversely correlated with VEGF expression in clinical breast cancer tissues, and FOXP3 downregulation and VEGF upregulation were both correlated with reduced survival in breast cancer data sets in the Kaplan-Meier plotter. Taken together, our data demonstrate that FOXP3 suppresses breast cancer angiogenesis by downregulating VEGF expression.
叉头框蛋白 P3（FOXP3）是一种 X 连锁的肿瘤抑制基因，在乳腺癌中发挥着重要作用。然而，FOXP3 在乳腺癌血管生成中的生物学功能尚不清楚。在这里，我们发现核 FOXP3 的临床表达与乳腺癌血管生成呈负相关。此外，动物研究表明，FOXP3 显著降低了 MDA-MB-231 肿瘤在小鼠体内的微血管密度。细胞学实验表明，FOXP3 过表达细胞的上清液在体外显著降低了对 HUVEC 管形成和发芽的刺激能力。此外，FOXP3 在乳腺癌细胞系中下调了血管内皮生长因子（VEGF）的表达。荧光素酶报告基因检测和染色质免疫沉淀检测表明，FOXP3 可以通过特异性叉头结合基序直接与 VEGF 启动子相互作用，抑制其转录。重要的是，体外添加 VEGF 可以逆转 FOXP3 在上清液中对 HUVEC 管形成和发芽的抑制作用。临床乳腺癌组织中核 FOXP3 的表达与 VEGF 的表达呈负相关，FOXP3 的下调和 VEGF 的上调均与 Kaplan-Meier 绘图器中乳腺癌数据集的生存时间缩短相关。综上所述，我们的数据表明，FOXP3 通过下调 VEGF 的表达抑制乳腺癌血管生成。
