REPRESSION OF THE INSULIN-RECEPTOR PROMOTER BY THE TUMOR-SUPPRESSOR GENE-PRODUCT P53 - A POSSIBLE MECHANISM FOR RECEPTOR OVEREXPRESSION IN BREAST-CANCER

There is strong evidence to suggest that insulin and insulin-like grow th factor (IGF)-I may be important for tumor growth, Both the insulin and IGF-I receptors (IGF-IR) are overexpressed in breast cancer, and a ntibody blockade of the IGF-IR inhibits the growth of some breast canc er cell lines, Furthermore, expression of an insulin receptor (IR) in a normal mammary epithelial cell line causes insulin-dependent transfo rmation, Functional inactivation of p53 is also very frequent in many tumors. In this paper, we investigated whether inactivation of p53 mig ht be involved in the overexpression of the IR in malignancy; specific ally breast cancer, We demonstrate a positive correlation between IR a nd IGF-IR levels and p53 overexpression in primary human breast malign ancies, To examine possible mechanisms by which p53 may regulate IR ge ne expression, we show that p53 can repress the IR promoter and that a dominant-negative p53 (248Q) can de-repress the promoter in cells con taining normal p53. The p53 effect was shown to be mediated by C/EBP a nd Sp1 transcription factors, We also documented that p53-null mice ha d elevated levels of Sp1, but not C/EBP alpha, and that insulin bindin g to liver extracts was increased compared to wild-type controls, Thes e results suggest that p53 inactivation mag lead to an up-regulation o f genes, such as the IR, that are dependent on these transcription fac tors.