TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis

Wenlong Ren; Huichun Liang; Jian Sun; Zhuo Cheng; Wenjing Liu; Yingying Wu; Yujie Shi; Zhongmei Zhou; Ceshi Chen

doi:10.1038/s41419-024-07223-2

TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis

Cell Death Dis. 2024 Nov 13;15(11):821. doi: 10.1038/s41419-024-07223-2.

Authors

Wenlong Ren^#^{1

2}, Huichun Liang^#², Jian Sun³, Zhuo Cheng², Wenjing Liu³, Yingying Wu⁴, Yujie Shi⁵, Zhongmei Zhou⁶, Ceshi Chen^{7

8

9}

Affiliations

¹ School of Life Science, University of Science & Technology of China, Hefei, Anhui, China.
² 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.
³ Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
⁴ Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
⁵ Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, China. [email protected].
⁶ The School of Continuing Education, Kunming Medical University, Kunming, China. [email protected].
⁷ 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. [email protected].
⁸ Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China. [email protected].
⁹ Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, ChinaAcademy of Biomedical Engineering, Kunming Medical University, Kunming, China. [email protected].

^# Contributed equally.

Abstract

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.

MeSH terms

Angiogenesis
Animals
Cell Line, Tumor
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Expression Regulation, Neoplastic
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
MAP Kinase Signaling System / drug effects
Mice
Mice, Inbred BALB C
Mice, Nude*
Neovascularization, Pathologic* / genetics
Neovascularization, Pathologic* / metabolism
Neovascularization, Pathologic* / pathology
Nitriles / pharmacology
Pyridines / pharmacology
Pyridones / pharmacology
Pyrimidinones / pharmacology
Signal Transduction*
Transcription Factor AP-1 / metabolism
Transcription, Genetic / drug effects
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
rac1 GTP-Binding Protein* / genetics
rac1 GTP-Binding Protein* / metabolism

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
rac1 GTP-Binding Protein
HIF1A protein, human
RAC1 protein, human
Transcription Factor AP-1
Pyrimidinones
Pyridines
apatinib
trametinib
Pyridones
Extracellular Signal-Regulated MAP Kinases
Nitriles