EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer.
BACKGROUND
PolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. This histone mark recruits the BMI1-containing PRC1 that silences the genes marked by PRC2. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients.


METHODS
We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples.


RESULTS
Interestingly, although EZH2 overexpression correlates with a poor prognosis in breast cancer, BMI1 overexpression correlates with a good outcome. Although this may reflect transformation of different cell types, we also observed a functional difference. The PcG-target genes INK4A and ARF are not expressed in tumours with high BMI1, but they are expressed in tumours with EZH2 overexpression. ARF expression results in tumour protein P53 (TP53) activation, and we found a significantly higher proportion of TP53 mutations in tumours with high EZH2. This may explain why tumours with high EZH2 respond poorly to therapy, in contrast to tumours with high BMI1.


CONCLUSIONS
Overall, our data highlight that whereas EZH2 and BMI1 may function in a 'linear' pathway in normal development, their overexpression has different functional consequences for breast tumourigenesis.
Pietersen
Alexandra M
AM
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066X, The Netherlands.
Horlings
Hugo M
HM
Hauptmann
Michael
M
Langerød
Anita
A
Ajouaou
Abderrahim
A
Cornelissen-Steijger
Paulien
P
Wessels
Lodewijk F
LF
Jonkers
Jos
J
van de Vijver
Marc J
MJ
van Lohuizen
Maarten
M
D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D020823:ADP-Ribosylation Factor 1