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Cancer Res. 2018 Aug 1;78(15):4316-4330. doi: 10.1158/0008-5472.CAN-18-1102. Epub 2018 Jul 19.

Loss of XIST in Breast Cancer Activates MSN-c-Met and Reprograms Microglia via Exosomal miRNA to Promote Brain Metastasis.

Author information

1
Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, North Carolina. kwatabe@wakehealth.edu fxing@wakehealth.edu.
2
Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, North Carolina.
3
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
4
Mammary Department, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
5
Department of Radiation Oncology, Wake Forest School of Medicine, Winston Salem, North Carolina.
6
Department of Hematology & Oncology, Wake Forest School of Medicine, Winston Salem, North Carolina.
7
Biostatistical Sciences Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC.
#
Contributed equally

Abstract

Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XISThigh cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XISTlow breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.Significance: These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XISTlow tumor cells in the brain. Cancer Res; 78(15); 4316-30. ©2018 AACR.

PMID:
30026327
PMCID:
PMC6072593
DOI:
10.1158/0008-5472.CAN-18-1102
[Indexed for MEDLINE]
Free PMC Article

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