BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer
| Autor: | Shao Zhimin, Di Zhu, Jinpeng Pei, Yi Xiao, Qiaofeng Liu, Xiaoshuang Wang, Ker Yu, Rina Rosin-Arbesfeld, Tengfei Xiao, Yu-Xiong Feng, Ying Shi, Chenglong Liu, Yang Zhou, Mei Feng, Baosen Guo, Danyang Liu, Yi-Zhou Jiang, Mengxuan Yang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Mice Nude Triple Negative Breast Neoplasms CD8-Positive T-Lymphocytes Biology Metastasis Mice 03 medical and health sciences 0302 clinical medicine Immune system Tumor Microenvironment Genetics medicine Animals Humans Cytotoxic T cell Molecular Biology Triple-negative breast cancer Cell Proliferation Tumor microenvironment Wnt signaling pathway Cell migration medicine.disease DNA-Binding Proteins 030104 developmental biology 030220 oncology & carcinogenesis MCF-7 Cells Cancer research CD8 Transcription Factors |
| Zdroj: | Oncogene. 40:2982-2997 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to a lack of well-defined molecular targets. The Wnt/β-catenin pathway is known to be activated in many TNBC patients and BCL9 and BCL9L are important transcriptional co-activators of β-catenin, but whether inhibition of BCL9/BCL9L can suppress TNBC growth and the underlying mechanism are not fully understood. Here we demonstrate that the expression of BCL9 and BCL9L is directly correlated with malignancy in TNBC patient tumors and that BCL9 and BCL9L promote tumor cell growth, cell migration and metastasis in TNBC models. Mechanistically, we found that BCL9/BCL9L promotes tumorigenicity through both the Wnt and TGF-β pathways. Besides, BCL9/BCL9L expression inversely correlates with CD8+ T cell infiltration in TNBC and BCL9/BCL9L inhibits the infiltration of CD8+ T cells in the tumor microenvironment. hsBCL9CT-24, an inhibitor of BCL9/β-catenin peptides, promotes intratumoral infiltration of cytotoxic T cells, reducing regulatory T cells (Treg) and increasing dendritic cells (DCs). Inhibition of BCL9/BCL9L and TGF-β suppresses activity of Treg. TGF-β signaling increases tumor infiltration of cytotoxic CD8+ T cells. In accordance, genetic or pharmacological inhibition of BCL9/BCL9L synergizes with PD-1/L1 antibodies to inhibit tumor growth. In summary, these results suggest that targeting BCL9/BCL9L has a direct anti-tumor effect and also unleashes an anti-cancer immune response through inhibition of both Wnt and TGF-β signaling, suggesting a viable therapeutic approach for TNBC treatment. |
| Databáze: | OpenAIRE |
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