p53 family members and chemoresistance in cancer: what we know and what we need to know.

Resistance to chemotherapy remains a major obstacle to the successful management of many human cancers. Numerous genetic and epigenetic changes in the cancer cell may contribute to drug resistance. However, with the recognition of important roles for both p53 and its more recently described paralog p73 in mediating the activity of anti-cancer drugs, there has been increasing recognition that cellular resistance to such agents can and does arise through failure of p53 family member signalling. Abrogation of function in p53 occurs through point mutations which abolish DNA binding or by dominant negative inhibition by variants of p73 lacking the N-terminal transactivation domain. Conversely, the function of full-length transactivation-competent (TA)p73 variants expressing the transactivation domain is itself subject to trans-dominant inhibition by certain p53 mutants and, in some cancers, by transcriptional silencing. The specificity of target gene activation by p53 and TAp73 is modulated by transcriptional co-activators which thereby act as response modifiers. Changes in the activity/expression of co-activators may therefore cause an altered cellular response to p53/p73 activation. Despite these advances in understanding how cells respond to DNA damage in vitro, and how this is affected by molecular genetic changes which affect p53 family member signalling, the contribution of these to in vivo drug resistance has not been definitively established. Our major task now is to determine how these changes operate individually and collectively in vivo to produce the phenotype of clinical drug resistance, and how we can translate this knowledge into clinically useful strategies to improve the outcome of chemotherapy.