ALTERED P53 CONFORMATION - A NOVEL MECHANISM OF WILD-TYPE P53 FUNCTIONAL INACTIVATION IN A MODEL FOR EARLY HUMAN BREAST-CANCER

The p53 protein is a transcription factor that is frequently mutated i n human malignancies. Using the MCF10AT model for early human breast c ancer we show that P53 protein is unmutated indicating that mutations are not necessary for alterations in growth and morphology that accomp any preneoplastic stages of breast tumor progression. Although p53 pro tein is wild-type in cells of the MCF10AT model system, it exists pred ominantly in a conformationally altered state that is defective in its ability both to bind DNA in a sequence-specific manner and to induce transcriptional activation from the WAF-1 promoter. This contrasts wit h P53 from the non-tumorigenic parental MCF10A cells which is predomin antly conformationally normal and functionally active. The possibility that stabilized wild-type but conformationally altered P53 plays a ro le in the neoplastic progression of preneoplastic MCF10AT system cells is discussed.