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β-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells

Oncogene volume 40, pages 5854–5865 (2021)Cite this article

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Abstract

Breast cancer is the most frequently diagnosed cancer among women worldwide. Though advances in diagnosis and treatment have prolonged overall survival (OS) for patients with breast cancer, metastasis remains the major obstacles to improved survival for breast cancer patients. The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence. Therefore, understanding the molecular pathways sustaining BCSC properties and targeting BCSCs will ultimately improve breast cancer treatments. In this study, we found that activation of β-Catenin directly regulated CCL2 expression at the transcriptional level, and in turn promoted macrophages infiltration and M2 polarization. Moreover, macrophages co-cultured with breast cancer cells showed a significant increase in CCL2 expression and promoted β-Catenin-induced BCSCs properties, whereas depletion of CCL2 by adding neutralizing antibodies suppressed BSCSs properties. In addition, we found that β-Catenin-mediated CCL2 secretion recruited macrophages into tumor microenvironment and promoted breast cancer growth and metastasis in vivo. Clinically, we observed a significant positive correlation between β-Catenin, CCL2 and CD163 expression, and increased expression of β-Catenin, CCL2 and CD163 predicted poor prognosis in breast cancer. Furthermore, pharmacological inhibition of CCR2 and β-Catenin synergistically suppressed BCSC properties and breast cancer growth. Collectively, our findings suggested that β-Catenin-mediated CCL2 secretion forms a paracrine feedback loop between breast cancer cells and macrophages, which in turn promotes BCSC properties and supports breast cancer growth and metastasis. Targeting β-Catenin/CCL2 signaling might be an effective strategy for breast cancer therapy.

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Fig. 1: β-Catenin regulates CCL2 expression in breast cancer cells.
Fig. 2: β-Catenin/CCL2 axis promotes the recruitment and polarization of macrophages.
Fig. 3: β-Catenin-induced CCL2 forms a paracrine feedback loop between breast cancer cells and tumor-associated macrophages.
Fig. 4: CCL2-mediated crosstalk between breast cancer cells and tumor-associated macrophages is involved in β-Catenin-induced breast cancer stem cell properties.
Fig. 5: β-Catenin/CCL2 feedback loop promotes breast cancer growth and metastasis via recruiting macrophages in vivo.
Fig. 6: β-Catenin is associated with TAMs infiltration and malignant progression in breast cancer patients.
Fig. 7: Combined inhibition of CCR2 and β-Catenin synergistically suppresses breast cancer growth.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81702819, 81772825, 81972194), grants from Guangdong Natural Science Funds (2017A030313500, 2019A1515010113).

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  1. These authors contributed equally: Fan Zhang, Pan Li, Shuang Liu.

Authors and Affiliations

  1. Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Fan Zhang

  2. Guangzhou Key Laboratory of “Translational Medicine on Malignant Tumor Treatment”, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China

    Pan Li, Shuang Liu, Mingqiang Yang, Shanshan Zeng, Danyang Chen & Hao Liu

  3. Department of Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Junjian Deng

  4. School of basic medicine, Guangdong medical university, Zhanjiang, Guangdong, China

    Yanmei Yi

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Contributions

HL, YY, DC contributed to the study design. FZ, PL and SL performed experiments. MY, SZ and JD analyzed the data. HL, ZF, YY and DC wrote the paper.

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Zhang, F., Li, P., Liu, S. et al. β-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells. Oncogene 40, 5854–5865 (2021). https://doi.org/10.1038/s41388-021-01986-0

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