The role of p53 loss in human cancer progression and therapeutic response

Abstract

Understanding the roles somatic mutations play in cancer progression is a critical step towards the development of novel treatment strategies. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer. A non‐tumorigenic, human cell line model system to study p53 loss in the absence of other oncogenic changes has not been available. Such a model system is key to investigating the possible direct causal connection that p53 deficiency may have in human cancers and to discovering the potential therapeutic effects of such loss. To evaluate the relevance of p53 loss, we have generated a novel in vitro model system using somatic cell knock‐out technology. This knock‐out technology, involving targeted homologous recombination, has enabled us to delete p53 in the non‐tumorigenic epithelial cell line, MCF10A. The initial hypothesis to be tested is that loss of p53 will cause a non‐tumorigenic cell line to display a more oncogenic phenotype. Recently, the homozygous deletion of p53 in four MCF10A clones was confirmed. While MCF10A cells have the appropriate G1/S and G2/M checkpoint responses upon DNA damage, the p53‐/‐ clones display a defective G1/S phase checkpoint response. Further characterization of each clone is being performed to assess the utility of p53 loss as a potential biomarker to predict the therapeutic response of cells treated with current chemotherapeutic regimens.