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Signalling pathway for RKIP and Let‐7 regulates and predicts metastatic breast cancer
Author(s) -
Yun Jieun,
Frankenberger Casey A,
Kuo WenLiang,
Boelens Mirjam C,
Eves Eva M,
Cheng Nancy,
Liang Han,
Li WenHsiung,
Ishwaran Hemant,
Minn Andy J,
Rosner Marsha Rich
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.312
Subject(s) - metastasis suppressor , metastasis suppressor gene , metastasis , biology , cancer research , hmga2 , breast cancer , transcription factor , microrna , mmp1 , signal transduction , suppressor , gene , cancer , gene expression , microbiology and biotechnology , genetics
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.