LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker.

Abstract	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.
Authors	Dahu Chen, Yutong Sun, Yongkun Wei, Peijing Zhang, Abdol Hossein Rezaeian, Julie Teruya-Feldstein, Sumeet Gupta, Han Liang, Hui-Kuan Lin, Mien-Chie Hung, Li Ma
Journal	Nature medicine (Nat Med) Vol. 18 Issue 10 Pg. 1511-7 (Oct 2012) ISSN: 1546-170X [Electronic] United States
PMID	23001183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Biomarkers, Tumor LIFR protein, human Leukemia Inhibitory Factor Receptor alpha Subunit MIRN92 microRNA, human MicroRNAs Nuclear Proteins Phosphoproteins Transcription Factors YAP-Signaling Proteins YAP1 protein, human Protein Serine-Threonine Kinases
Topics	Adaptor Proteins, Signal Transducing (metabolism) Animals Biomarkers, Tumor Breast Neoplasms (genetics, metabolism) Cell Communication Cell Line, Tumor Cell Movement (genetics) Cell Proliferation Female High-Throughput Nucleotide Sequencing Humans Leukemia Inhibitory Factor Receptor alpha Subunit (genetics, metabolism) Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, SCID MicroRNAs (genetics) Neoplasm Invasiveness (genetics) Neoplasm Metastasis Nuclear Proteins (genetics, metabolism) Phosphoproteins (metabolism) Phosphorylation Prognosis Protein Serine-Threonine Kinases (metabolism) Sequence Analysis, RNA Signal Transduction Transcription Factors (genetics, metabolism) YAP-Signaling Proteins

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