Signalling pathway for RKIP and Let-7 regulates and predicts metastatic breast cancer

EMBO J. 2011 Aug 26;30(21):4500-14. doi: 10.1038/emboj.2011.312.


Tumour metastasis suppressors are inhibitors of metastasis but their mechanisms of action are generally not understood. We previously showed that the suppressor Raf kinase inhibitory protein (RKIP) inhibits breast tumour metastasis in part via let-7. Here, we demonstrate an integrated approach combining statistical analysis of breast tumour gene expression data and experimental validation to extend the signalling pathway for RKIP. We show that RKIP inhibits let-7 targets (HMGA2, BACH1) that in turn upregulate bone metastasis genes (MMP1, OPN, CXCR4). Our results reveal BACH1 as a novel let-7-regulated transcription factor that induces matrix metalloproteinase1 (MMP1) expression and promotes metastasis. An RKIP pathway metastasis signature (designated RPMS) derived from the complete signalling cascade predicts high metastatic risk better than the individual genes. These results highlight a powerful approach for identifying signalling pathways downstream of a key metastasis suppressor and indicate that analysis of genes in the context of their signalling environment is critical for understanding their predictive and therapeutic potential.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Biomarkers, Tumor / physiology
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma / diagnosis*
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Microarray Analysis
  • Models, Biological
  • Neoplasm Metastasis
  • Phosphatidylethanolamine Binding Protein / genetics
  • Phosphatidylethanolamine Binding Protein / metabolism
  • Phosphatidylethanolamine Binding Protein / physiology*
  • Prognosis
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Biomarkers, Tumor
  • MicroRNAs
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • mirnlet7 microRNA, human