| 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. © 2012 Nature America, Inc. All rights reserved. |
| Keywords: |
signal transduction; controlled study; protein expression; protein phosphorylation; unclassified drug; overall survival; nonhuman; cell proliferation; animal cell; mouse; animals; mice; animal tissue; metastasis; breast cancer; yes associated protein; tumor markers, biological; protein; mice, scid; cell line, tumor; breast neoplasms; phosphorylation; tumor marker; mice, inbred balb c; transcription factors; nuclear proteins; cancer invasion; protein-serine-threonine kinases; cancer cell; tumor cell; neoplasm metastasis; cell movement; neoplasm invasiveness; micrornas; sequence analysis, rna; mice, inbred nod; cell communication; phosphotransferase; recurrence free survival; microrna 9; high-throughput nucleotide sequencing; hippo kinase; leukemia inhibitory factor receptor; leukemia inhibitory factor receptor alpha subunit
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