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 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.
Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia. Paul.Neilsen@health.sa.gov.au
P M
PM
Neilsen
J E
JE
Noll
S
S
Mattiske
C P
CP
Bracken
P A
PA
Gregory
R B
RB
Schulz
S P
SP
Lim
R
R
Kumar
R J
RJ
Suetani
G J
GJ
Goodall
D F
DF
Callen
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D053263:Gene Regulatory Networks; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*
D014408:Biomarkers, Tumor; C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; C524942:MIRN155 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; C525993:ZNF652 protein, human