School of Life Science, University of Science & Technology of China, Hefei, Anhui, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Cell Death Dis. 2024 Nov 13;15(11):821. doi: 10.1038/s41419-024-07223-2.
Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown. In this study, we demonstrated that TNFAIP2 promotes TNBC angiogenesis by activating the Rac1-ERK-AP1-HIF1α signaling axis. Under hypoxia, TNFAIP2 activates Rac1 and ERK sequentially. Following that, ERK activates the AP-1 (c-Jun/Fra1) transcription factor. By employing chromatin immunoprecipitation and luciferase reporter assays, we showed that AP-1 directly interacts with the HIF1α gene promoter, thereby enhancing its transcription. The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.
血管生成在乳腺癌中起着至关重要的作用。我们之前的研究表明，TNFAIP2 通过激活 Rac1 促进三阴性乳腺癌（TNBC）细胞的增殖、迁移和化疗耐药性。然而，TNFAIP2 对肿瘤血管生成的潜在贡献尚不清楚。在这项研究中，我们证明 TNFAIP2 通过激活 Rac1-ERK-AP1-HIF1α 信号轴促进 TNBC 血管生成。在缺氧条件下，TNFAIP2 依次激活 Rac1 和 ERK。随后，ERK 激活 AP-1（c-Jun/Fra1）转录因子。通过染色质免疫沉淀和荧光素酶报告基因分析，我们表明 AP-1 直接与 HIF1α 基因启动子相互作用，从而增强其转录。联合应用 ERK 抑制剂 U0126 或 trametinib 与 VEGFR 抑制剂阿帕替尼，可显著抑制裸鼠 HCC1806 中的血管生成和肿瘤生长。这些发现为 TNBC 提供了新的治疗策略。
