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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Macrophages and cancer stem cells: a malevolent alliance
Molecular Medicine Open Access 28 September 2021
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This work was supported by the National Natural Science Foundation of China (81702819, 81772825, 81972194), grants from Guangdong Natural Science Funds (2017A030313500, 2019A1515010113).
The authors declare no competing interests.
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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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