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Abstract
Neutrophil extracellular traps (NETs) has been demonstrated to regulate the metastasis of breast cancer. In this study, we showed that de novo cholesterol biosynthesis induced by ASPP2 depletion in mouse breast cancer cell 4T1 and human breast cancer cell MDA-MB-231 promoted NETs formation in vitro, as well as in lung metastases in mice intravenously injected with ASPP2-deficient 4T1 cells. Simvastatin and berberine (BBR), cholesterol synthesis inhibitors, efficiently blocked ASPP2-depletion induced NETs formation. Cholesterol biosynthesis greatly enhanced Coiled-coil domain containing protein 25 (CCDC25) expression on cancer cells as well as in lung metastases. CCDC25 expression was co-localized with caveolin-1, a lipid raft molecule, and was damped by inhibitor of lipid rafts formation. Our data suggest that cholesterol biosynthesis promotes CCDC25 expression in a lipid raft-dependent manner. Clinically, the expression of CCDC25 was positively correlated with the expression of 3-hydroxy-3-methylglutaryl-CoAreductase (HMRCG), and citrullinated histone H3 (H3cit), in tissues from breast cancer patients. High expression of CCDC25 and HMGCR was related with worse prognosis in breast cancer patients. In conclusion, our study explores a novel mechanism for de novo cholesterol biosynthesis in the regulation of CCDC25 expression, NETs formation and breast cancer metastasis. Targeting cholesterol biosynthesis may be promising therapeutic strategies to treat breast cancer metastasis.
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1 Shanghai University of Medicine and Health Science, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277); Shanghai University of Traditional Medicine, Shanghai, China (GRID:grid.39436.3b) (ISNI:0000 0001 2323 5732)
2 Shanghai University of Medicine and Health Science, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277); Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277)
3 Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277)
4 Navy Military Medical University, Changhai Hospital, Shanghai, China (GRID:grid.411525.6) (ISNI:0000 0004 0369 1599)
5 University of Oxford, Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948)
6 Fudan University, Phase I Clinical Trial Center, Shanghai Cancer Center, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Fudan University, Department of Oncology, Shanghai Medical College, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443)
7 Shanghai University of Medicine and Health Science, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277); Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai Key Laboratory of Molecular Imaging, Shanghai, China (GRID:grid.507037.6) (ISNI:0000 0004 1764 1277); Shanghai University of Traditional Medicine, Shanghai, China (GRID:grid.39436.3b) (ISNI:0000 0001 2323 5732)