ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine
Jun Xu, … , Chu-Xia Deng, Xiaoling Xu
Jun Xu, … , Chu-Xia Deng, Xiaoling Xu
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e149473. https://doi.org/10.1172/JCI149473.
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Research Article Oncology

ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine

Abstract

Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no expression or low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that cells with low ATP11B expression and high PTDSS2 expression (ATP11BloPTDSS2hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11BloPTDSS2hi phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressor cells and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11BloPTDSS2hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11BhiPTDSS2lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11BloPTDSS2hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.

Authors

Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh Haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu

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Figure 3

PS displacement on outer leaflet of the cell membrane is regulated by ATP11B and BRCA1.

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PS displacement on outer leaflet of the cell membrane is regulated by AT...
(A) PS displacement on the cell membrane by FACS with anti-PS antibody in WT and Brca1-MT primary mammary epithelial cells (n = 4 pairs) and 545, MDA-MB-436, and T47D cells without or with sgATP11B expression. (B) Quantification for A. (C) Apoptotic cells in WT and Brca1-MT primary mammary epithelial cells (n = 4 pairs) and 545, MDA-MB-436, and T47D cells without or with sgATP11B expression by FACS using the APO-BrdU Kit. (D) Quantification for C. (E) Protein levels of cleaved caspase-3 in WT (B477) and Brca1-MT (G600) mammary epithelial cells and 545 Brca1-MT tumor cells without or with sgATP11b expression. (F) Representative images of PS displacement in 628 parental cells and 628 cells with sgATP11b expression, overexpression (OE) of ATP11b, and OE-Brca1 stained with PS antibody and DAPI, imaged by Zeiss LSM 880 high-resolution microscope with Airyscan (n = 3 times). Scale bars: 5 μm. (G and H) Brca1, ATP11b, and Ptdss2 expression in 545 cells without (red) or with mBrca1 cDNA expression (green) by qPCR (G) and protein levels by Western blot (n = 3 times) (H). (I and J) PS displacement on cell membrane of 545 cells without (red) or with (blue) mBrca1 cDNA expression by FACS analysis (I), and quantification (J) (n = 3 times). (K and L) hBRCA1, ATP11B, and PTDSS2 expression in T47D cells without (red) or with hBRCA1 cDNA expression (green) by qPCR (K), and protein levels by Western blot (n = 3 times) (L). (M and N) PS displacement on cell membrane of T47D cells without or with hBRCA1 cDNA expression by FACS (M), and quantification (N) (n = 3 times). Error bars show mean ± SEM of 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.