Whole genome sequencing of human cancers has confirmed that mutations in the p53 gene are the most common specific genetic events in human cancer. The strength of the data base is now such that we can be sure that this is a final answer. What then does p53 mutation do that is so important and how might we exploit this knowledge for the improved diagnosis and treatment of cancer?
The p53 protein is a highly regulated master transcription factor that is induced by stress and in particular by DNA damage. It induces a complex pattern of transcription that activates cellular repair pathways as well as cell cycle arrest and apoptotic processes all of which act to prevent cancer formation.
Intense study of the p53 pathway in breast cancer has shown that germ line mutations in p53 are a very important genetic risk factor like the BRCA 1 and BRCA 2 genes but perhaps not so well known in this context .
In triple negative breast cancers point mutations in the p53 protein are common and therapies aimed at exploiting loss of p53 activity, or that reactivate mutant p53 to wild type function are appropriate. IN addition many point mutations in p53 convert it into a driver oncogenes so strategies to block its expression are also being tested.In contrast in many other forms of breast cancer p53 is not mutated but is inactivated by alterations in signalling pathways that are still not well understood. Drugs that can bypass these signalling defects are now in clinical trial and offer considerable promise but need to be refined and made more selective. In a new approach we have been engineering peptides to regulate p53 using novel chemical methods to help the peptides enter cells and stably engage their targets.
Using mice homozygous for mutant p53 and mice treated with proteosome inhibitors to stabilize p53 we have carried out an extensive investigation of the regulation of p53 expression in normal and pre neoplastic mouse tissue. Interestingly the p53 gene is only transcribed in proliferating cells and the gene is rapidly turned off as cell differentiate and exit the cell cycle. Protein expression levels are very modest and high levels of expression are only reached in tumor cells and in some pre neoplastic conditions.