The p53 tumor suppressor plays a pivotal role in the prevention of neoplastic transformation, with half of all human tumours harbouring mutations in TP53. Such mutations not only lead to the expression of a protein unable to impart its normal tumour suppressor ability, but also endow the mutant p53 protein with newly acquired oncogenic properties that drive invasion and metastasis. Although it is widely established that mutant p53-expressing tumours have a high capacity to metastasize and are associated with poor outcomes, the key molecular mechanisms utilised by mutant p53 are largely unknown.
We have developed a panel of H1299 carcinoma derivatives that can inducibly re-express various mutant p53 proteins into a p53 null background. Induction of mutant p53 in the primary H1299 xenograft tumour was associated with increased distant metastases, drove an EMT-like phenotype and was associated with an increase invasive capacity1,2. We show that mutant p53 functions as an aberrant transcription factor to selectively alter the expression of key cancer-related genes3. ChIP studies revealed that mutant p53 forms an oncogenic complex with p63 at the promoters of p63 target genes, resulting in disruption of the anti-metastatic p63-signalling pathway. Key direct targets of mutant p53-p63 axis include PLK2, DKK1 and miR-1554. Surprisingly, the majority of mutant p53 target genes were secreted products. This aberrant secretome driven by mutant p53 stimulated invasive properties in recipient cell lines, thus providing a novel mechanism for mutant p53 to promote invasion.