Restoration of p53 function leads to tumour regression in vivo

• Published in: Nature Vol. 445; no. 7128; pp. 661 - 665
• Main Authors: Jacks, Tyler, Ventura, Andrea, Kirsch, David G, McLaughlin, Margaret E, Tuveson, David A, Grimm, Jan, Lintault, Laura, Newman, Jamie, Reczek, Elizabeth E, Weissleder, Ralph
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 08.02.2007; Nature Publishing Group
• Subjects: Alleles; Animal tumors. Experimental tumors; Animals; Apoptosis; Biological and medical sciences; Cancer; Cell Division; Cellular Senescence; Disease Models, Animal; Drug therapy; Experimental malignant blood diseases; Experimental tumors, general aspects; Gene expression; Genotype & phenotype; Humans; Inactivation; Lymphoma - metabolism; Lymphoma - pathology; Medical sciences; Mice; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Organ Specificity; Rodents; Sarcoma - metabolism; Sarcoma - pathology; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Sarcoma; Rodentia; Regression; Malignant hemopathy; Malignant tumor; Lymphoid neoplasm; Lymphoma; Vertebrata; Mammalia; TP53 Gene; Mouse; Lymphoproliferative syndrome; Animal; Genetics; Tumor suppressor gene
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05541

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.