Mutations in the tumour suppressor p53 occur in ~50% of human cancers. Many of these mutations cause p53 protein to abnormally accumulate in the malignant cells, making it an enticing therapeutic target. However, for these therapies to be effective, the tumour cells must rely on the proposed “gain-of-function” effects ascribed to mutant p53 (de novo functions that wildtype p53 does not exhibit). However, the importance of these gain-of-function effects and whether they truly exist are still being debated.
We aim to investigate if tumours rely on these gain-of-function effects by generating a pair of switchable mutant p53 mouse lines, that express wildtype p53 in all cells of the body from conception. FLP-mediated recombination can induce expression of a mutant p53 protein in specifically targeted cells. In the first mouse strain, following CRE-mediated gene recombination wildtype p53 protein expression can be restored. In the second strain, CRE recombination converts the mutant p53 expressing cells into a p53 knockout state. By studying how the tumours react after CRE recombination, we can answer whether or not gain-of-function effects are critical for cancer cell survival.
We validated the system in fibroblasts showing we can induce the expression of mutant p53, and subsequently remove mutant p53 at will. Mice expressing the mutant protein from conception develop spontaneous tumours at a rate equivalent to p53 knockout animals. To study lymphoma, we have crossed these mice onto an Eµ-Myc background, which promotes the development of pre-B/B lymphomas that are accelerated by mutation of p53. We also plan to study tumorigenesis in other cancer types such as lung, pancreas, and colorectal.
These switchable mutant p53 mouse models have the potential to answer some of the most important open questions in the field, such as whether removing mutant p53 protein or restoring wildtype p53 function will influence tumour growth and thus have therapeutic impact. This is important knowledge for the development of improved therapies for cancers with p53 mutations.