Publication: Deciphering The Mechanism Of Mutant P53 'Gain-Of-Function' Effects In Human Breast Cancers
| dc.contributor.author | Tan Boon Shing | |
| dc.date.accessioned | 2023-10-06T15:26:17Z | |
| dc.date.available | 2023-10-06T15:26:17Z | |
| dc.date.issued | 2012 | |
| dc.description.abstract | The p53 is the most commonly mutated tumour suppressor gene in human cancers. Unlike other tumour suppressor genes, most p53 cancer mutations are missense mutations leading to the expression of full-length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumour suppression activity, but also gain new oncogenic activities to promote tumourigenesis. Given the active role of mutant p53 proteins in promoting tumourigenesis and their very common occurrence in breast cancer, identification of pathways regulated by distinct classes of mutant p53 proteins may provide new therapeutic targets that would improve the treatment of patients with p53-mutated breast cancers. By employing RNA interference (RNAi) approach, this study has provided direct evidence to support the oncogenic role of mutant p53 in human breast cancers. This study shows that silencing of endogenous p53 R 273H contact mutant in MDA-MB-46 8 cells induced massive apoptosis while no apoptosis was observed in the silencing of the p53 R175H structural mutant in SKBR-3 cells. Further analysis showed that the apoptotic effects of mutant p53 knock-down involved activation of caspase 9 and mitochondria depolarisation, suggesting a role of mutant p53 in suppressing the intrinsic apoptotic pathway. Indeed, a BCL-2 family member, BCL-2 modifying factor (BMF), was reproducibly up-regulated following knock-down of mutant p53 in MDA- MB-468 cells while no significant changes were observed in other BCL-2 family members. The functional role of this up-regulation was further interrogated by ectopic expression of BMF in MDA-MB- 468 cells which was shown to be capable of inducing massive apoptosis. Finally, depletion of BMF in MDA-MB-468 cells completely abrogated the apoptotic effects of mutant p53 knock-down, suggesting a role of mutant p53 in mediating the survival of breast cancer cells through the suppression of BMF expression. | en_US |
| dc.identifier.uri | https://hdl.handle.net/20.500.14377/32169 | |
| dc.language.iso | en | en_US |
| dc.publisher | International Medical University | en_US |
| dc.subject | Breast Neoplasms | en_US |
| dc.subject | Genes, p53 | en_US |
| dc.subject | Tumor Suppressor Protein p53 | en_US |
| dc.subject | RNA Interference | en_US |
| dc.title | Deciphering The Mechanism Of Mutant P53 'Gain-Of-Function' Effects In Human Breast Cancers | en_US |
| dc.type | Thesis | |
| dspace.entity.type | Publication |