期刊
NATURE MEDICINE
卷 18, 期 10, 页码 1511-U105出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2940
关键词
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资金
- US National Institutes of Health [R00CA138572, R01CA166051, R01CA109311, P01CA099031]
- Cancer Prevention and Research Institute of Texas Scholar Award [R1004]
- University of Texas STARS Award
- Faculty Development Award
- MD Anderson Cancer Center from the US National Institutes of Health, Center for Biological Pathways [CA016672]
- Susan G. Komen for the Cure grant [SAC110016]
- National Breast Cancer Foundation, Inc.
- China Medical University and Hospital
- MD Anderson Cancer Center
There is a pressing need to identify prognostic markers of metastatic disease and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the microRNA miR-9 and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention and functional inactivation of the transcriptional coactivator YES-associated protein (YAP). Conversely, loss of LIFR in nonmetastatic breast cancer cells induces migration, invasion and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, in approximately 1,000 nonmetastatic breast tumors, LIFR expression status correlated with metastasis-free, recurrence-free and overall survival outcomes in the patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power.
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