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BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer

Oncogene volume 40, pages 2982–2997 (2021)Cite this article

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Abstract

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.

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Fig. 1: BCL9 expression is associated with malignant TNBC phenotypes.
Fig. 2: BCL9 expression correlates with immune cell tumor infiltration.
Fig. 3: BCL9 promotes tumor growth and experimental liver metastasis in TNBC mouse models.
Fig. 4: Depletion of BCL9 and BCL9L promotes infiltration of CD8+ T cells in the tumor microenvironment and synergizes with PD-1 antibody to attenuate TNBC progression.
Fig. 5: BCL9 mediates TGF-β pathway expression in TNBC cells.
Fig. 6: Inhibition of Bcl9 modulates tumor immune microenvironment and reactivates anticancer immunity.

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Data availability

The datasets analyzed during the current study are available in the figshare repository at https://figshare.com/s/c5c6f110b566dadced09.

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Funding

The current study was supported by projects on the National Natural Science Foundation of China (81373442) (KY), National Science and Technology Major Project of China (2018ZX09711002–008) (KY), the National Basic Research Program (973 Program) of China (2013CB932500) (KY), the Science and Technology Commission of Shanghai (18ZR1403900, 18JC1413800) (DZ), the National Natural Science Foundation of China (81872895) (DZ), and the project on joint translational research in the School of Pharmacy and Minhang Hospital (RO-MY201712) (DZ).

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  1. These authors contributes equally: Xiaoshuang Wang, Mei Feng

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China

    Xiaoshuang Wang, Mei Feng, Chenglong Liu, Jinpeng Pei, Qiaofeng Liu, Ying Shi, Yang Zhou, Ker Yu & Di Zhu

  2. XBH Biotech, Shanghai, China

    Tengfei Xiao

  3. Shenzhen Digital Life Institute, Shenzhen, Guangdong, China

    Baosen Guo

  4. Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China

    Danyang Liu

  5. Department of Surgery in Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai, China

    Yi Xiao, Yizhou Jiang & Zhimin Shao

  6. Department of Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Rina Rosin-Arbesfeld

  7. The First Affiliated Hospital, Zhejiang University School of Medicine, Institute of Translational Medicine, Zhejiang University, Hangzhou, China

    Mengxuan Yang & Yu-Xiong Feng

  8. Fudan affiliated Zhongshan Hospital Minhang Branch, and Key Laboratory of Smart Drug Delivery, Fudan University, Shanghai, China

    Di Zhu

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Wang, X., Feng, M., Xiao, T. et al. BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer. Oncogene 40, 2982–2997 (2021). https://doi.org/10.1038/s41388-021-01756-y

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