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Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs

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Abstract

Breast cancer is the leading cause of death in female cancer patients due to the lack of effective treatment for metastasis. Macrophages are the most abundant immune cells in the primary and metastatic tumors, and contribute to tumor initiation, progression, and metastasis. Emodin has been found to exert anti-tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during cancer metastasis have not been investigated. Mice inoculated with 4T1 or EO771 breast cancer cells orthotopically were treated with Emodin after the primary tumors reached 200 mm3 in size. Primary tumor growth, lung metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of Emodin on macrophage migration and M2 polarization, and the underlying mechanisms. Emodin significantly suppressed breast cancer lung metastasis in both orthotopic mouse models without apparent effects on primary tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in Emodin-treated mice. In vitro experiments demonstrated that Emodin decreased the migration of macrophages toward tumor cell-conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically, Emodin suppressed STAT6 phosphorylation and C/EBPβ expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with IL-4 or TCM. Taken together, our study, for the first time, demonstrated that Emodin suppressed pulmonary metastasis of breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPβ expression.

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Acknowledgments

This work was supported by grants NIH R21AT006767 and R01HL116626 (to DF).

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No potential conflicts of interest were disclosed.

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Correspondence to Daping Fan.

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Jia, X., Yu, F., Wang, J. et al. Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs. Breast Cancer Res Treat 148, 291–302 (2014). https://doi.org/10.1007/s10549-014-3164-7

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  • DOI: https://doi.org/10.1007/s10549-014-3164-7

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