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

Nat Med. 2012 Oct;18(10):1511-7. doi: 10.1038/nm.2940. Epub 2012 Sep 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Biomarkers, Tumor
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Communication
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leukemia Inhibitory Factor Receptor alpha Subunit / genetics
  • Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Prognosis
  • Protein-Serine-Threonine Kinases / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • MIRN92 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Protein-Serine-Threonine Kinases