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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 Article has an altmetric score of 2

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

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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 4

Ptdss2 is negatively regulated by Brca1.

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Ptdss2 is negatively regulated by Brca1.
(A) The top 10 biological proc...
(A) The top 10 biological processes in Brca1-MT mammary tissues annotated by GO analysis with comparison of RNA-Seq from MTMG, PT, and LMT of Brca1-MSK mice versus WTMG (n = 3 mice per group). (B) Ptdss2 expression in WT lung and metastatic and primary tumors (n = 3 mice per group). (C) Expression of PTDSS2 in human breast cancer patients with or without metastasis compared with healthy donors in TCGA-BRCA database (healthy donors, n = 122; non-metastatic patients, n = 623; metastatic patients, n = 9). (D) Ptdss2 expression from bulk RNA-Seq in lung, LMT, and PT compared with WT controls (n = 3 mice per group). RSEM, RNA-Seq by Expectation–Maximization. (E) Protein levels of PTDSS2 in WTMG, MTMG, PT, and LMT by Western blot (n = 3 times). (F and G) Protein levels of PTDSS2 in both mammary gland (F) and tumors (G) with age-matched WTMG (n = 3 mice) and MTMG (n = 10 mice), WT tumor (n = 3 mice), and PT from Brca1-MSK mice (n = 11 mice) by Western blot (n = 3 times). (H) Ptdss2 promoter activity assay in G600, B477, and 545 cells without or with expression of mBrca1 cDNA or mPtdss2 cDNA (n = 3 times). (I and J) Expression of Brca1 and Ptdss2 by qPCR (I) and Western blot (J) in B477 cells without (red) or with (green) shBrca1 cDNA (n = 3 times). Statistical data in B–D were assessed using 1-way ANOVA with Bonferroni’s multiple-comparison test; data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

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