Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

Loss of p53 function is a critical event during tumorigenesis, with half of all cancers harboring mutations within the TP53 gene. Such events frequently result in the expression of a mutated p53 protein with gain-of-function properties that drive invasion and metastasis. Here, we show that the expre...

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Bibliographic Details
Published in:	Oncogene Vol. 32; no. 24; pp. 2992 - 3000
Main Authors:	Neilsen, P M, Noll, J E, Mattiske, S, Bracken, C P, Gregory, P A, Schulz, R B, Lim, S P, Kumar, R, Suetani, R J, Goodall, G J, Callen, D F
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 13-06-2013 Nature Publishing Group
Subjects:	631/337/384/331 631/80/86 692/699/67/1347 692/699/67/322 Apoptosis Biomarkers, Tumor - metabolism Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Breast tumors Cancer Cell Biology Cell Line, Tumor Cell Movement - genetics DNA-Binding Proteins - metabolism Epithelial Cells - metabolism Epithelial Cells - pathology Epithelial-Mesenchymal Transition - genetics Gene mutations Gene Regulatory Networks Genetic aspects Genetic regulation Health aspects Human Genetics Humans Internal Medicine Medicine Medicine & Public Health Membrane Proteins - metabolism Metastases Metastasis MicroRNA MicroRNAs - genetics miRNA Mutant Proteins - genetics Mutant Proteins - metabolism Mutants Mutation Neoplasm Invasiveness Oncology original-article p53 Protein Physiological aspects Signal Transduction - genetics Smad2 protein Transcription Transforming growth factor-b1 Tumor cell lines Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumorigenesis Tumors Up-Regulation - genetics Zinc finger proteins Australia mutant p53 breast cancer invasion miR-155 ZNF652
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Summary:	Loss of p53 function is a critical event during tumorigenesis, with half of all cancers harboring mutations within the TP53 gene. Such events frequently result in the expression of a mutated p53 protein with gain-of-function properties that drive invasion and metastasis. Here, we show that the expression of miR-155 was up-regulated by mutant p53 to drive invasion. The miR-155 host gene was directly repressed by p63, providing the molecular basis for mutant p53 to drive miR-155 expression. Significant overlap was observed between miR-155 targets and the molecular profile of mutant p53-expressing breast tumors in vivo . A search for cancer-related target genes of miR-155 revealed ZNF652, a novel zinc-finger transcriptional repressor. ZNF652 directly repressed key drivers of invasion and metastasis, such as TGFB1 , TGFB2, TGFBR2, EGFR, SMAD2 and VIM. Furthermore, silencing of ZNF652 in epithelial cancer cell lines promoted invasion into matrigel. Importantly, loss of ZNF652 expression in primary breast tumors was significantly correlated with increased local invasion and defined a population of breast cancer patients with metastatic tumors. Collectively, these findings suggest that miR-155 targeted therapies may provide an attractive approach to treat mutant p53-expressing tumors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2012.305