Mutant p53 mediates survival of breast cancer cells.
BACKGROUND
p53 is the most commonly mutated tumour-suppressor gene in human cancers. Unlike other tumour-suppressor genes, most p53 cancer mutations are missense mutations within the core domain, leading to the expression of a full-length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose tumour suppression activity but also gain new oncogenic activities to promote tumourigenesis.


METHODS
The endogenous mutant p53 function in human breast cancer cells was studied using RNA interference (RNAi). Gene knockdown was confirmed by quantitative PCR and western blotting. Apoptosis was evaluated by morphological changes of cells, their PARP cleavage and annexin V staining.


RESULTS
We show that cancer-associated p53 missense mutants are required for the survival of breast cancer cells. Inhibition of endogenous mutant p53 by RNAi led to massive apoptosis in two mutant p53-expressing cell lines, T47D and MDA-MB-468, but not in the wild-type p53-expressing cells, MCF-7 and MCF-10A. Reconstitution of an RNAi-insensitive mutant p53 in MDA-MB-468 cells completely abolished the apoptotic effects after silencing of endogenous mutant p53, suggesting the specific survival effects of mutant p53. The apoptotic effect induced by mutant p53 ablation, however, is independent of p63 or p73 function.


CONCLUSIONS
These findings provide clear evidence of a pro-survival 'gain-of-function' property of a subset of p53 cancer mutants in breast cancer cells.
Lim
L Y
LY
International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Vidnovic
N
N
Ellisen
L W
LW
Leong
C-O
CO
D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins