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

Neilsen, P. M., Noll, J. E., Bracken, C. P., Gregory, P. A., Schulz, R. B., Lim, S. P., Kumar, R., Suetani, R. J., Goodall, G. J. and Callen, D. F. (2012) Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene, 32 24: 2992-3000. doi:10.1038/onc.2012.305


Author Neilsen, P. M.
Noll, J. E.
Bracken, C. P.
Gregory, P. A.
Schulz, R. B.
Lim, S. P.
Kumar, R.
Suetani, R. J.
Goodall, G. J.
Callen, D. F.
Title Mutant p53 drives invasion in breast tumors through up-regulation of miR-155
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2012-07-16
Sub-type Article (original research)
DOI 10.1038/onc.2012.305
Open Access Status Not Open Access
Volume 32
Issue 24
Start page 2992
End page 3000
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
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.
Keyword Breast cancer
Invasion
miR-155
mutant p53
ZNF652
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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Created: Mon, 30 Nov 2015, 19:32:35 EST by Rachel Suetani on behalf of Queensland Brain Institute