Tumor suppressor p53 regulates insulin receptor () gene expression via direct binding to the promoter.

A significant volume of clinical and epidemiological data provides support to the concept that insulin and the insulin receptor (INSR) have an important role in breast cancer. Tumor suppressor p53 is the most frequently mutated molecule in human cancer. The present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the gene in breast cancer cells. In addition, the study was designed to investigate the mechanism of action of p53 in the context of gene regulation. The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor (IGF1R) or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression. Data indicate that the gene constitutes a target for p53 action. Wild-type p53 stimulated promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53. Mutant p53 strongly stimulated promoter. Furthermore, p53 directly binds to the promoter in cells with a disrupted IGF1R. Combined, our results identified complex functional and physical interactions between p53 and the INSR pathway. The implications of the p53-INSR interplay in breast cancer needs to be further investigated.