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

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 combi...

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Bibliographic Details
Published in:The EMBO journal 2011-11, Vol.30 (21), p.4500-4514
Main Authors: Yun, Jieun, Frankenberger, Casey A, Kuo, Wen-Liang, Boelens, Mirjam C, Eves, Eva M, Cheng, Nancy, Liang, Han, Li, Wen-Hsiung, Ishwaran, Hemant, Minn, Andy J, Rosner, Marsha Rich
Format: Article
Language:English
Subjects:
Animals
BACH1
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Biomarkers, Tumor - physiology
Breast cancer
Breast Neoplasms - diagnosis
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Carcinoma - diagnosis
Carcinoma - genetics
Carcinoma - pathology
Cell Line, Tumor
Female
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
gene signature
Humans
Let-7
Metastasis
Mice
Microarray Analysis
MicroRNAs - genetics
MicroRNAs - metabolism
MicroRNAs - physiology
Models, Biological
Molecular biology
Neoplasm Metastasis
Phosphatidylethanolamine Binding Protein - genetics
Phosphatidylethanolamine Binding Protein - metabolism
Phosphatidylethanolamine Binding Protein - physiology
Prognosis
Proteins
RKIP
Signal transduction
Signal Transduction - genetics
Signal Transduction - physiology
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Summary: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. RKIP is a metastasis suppressor, acting via the microRNA let‐7 to inhibit invasiveness of breast cancer cells. The identification of relevant let‐7 target genes defines an RKIP pathway metastasis signature that is predictive of metastatic risk in breast cancer samples.
ISSN:0261-4189
1460-2075
DOI:10.1038/emboj.2011.312