TY - JOUR
T1 - LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker
AU - Chen, Dahu
AU - Sun, Yutong
AU - Wei, Yongkun
AU - Zhang, Peijing
AU - Rezaeian, Abdol Hossein
AU - Teruya-Feldstein, Julie
AU - Gupta, Sumeet
AU - Liang, Han
AU - Lin, Hui Kuan
AU - Hung, Mien Chie
AU - Ma, Li
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84870261155&partnerID=8YFLogxK
U2 - 10.1038/nm.2940
DO - 10.1038/nm.2940
M3 - Article
C2 - 23001183
AN - SCOPUS:84870261155
VL - 18
SP - 1511
EP - 1517
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 10
ER -