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

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

Research output: Contribution to journalArticle

262 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1511-1517
Number of pages7
JournalNature Medicine
Volume18
Issue number10
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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