1. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
2. Department of Radiation Oncology,
3. Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, Massachusetts 02129, USA, and Harvard Medical School, Boston, Massachusetts 02115, USA
4. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
5. These authors contributed equally to this work.

Correspondence to: Tyler Jacks^1,4 Correspondence and requests for materials should be addressed to T.J. (Email: tjacks@mit.edu).

Abstract

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes¹. 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^{2, 3, 4, 5}; this phenotype is referred to as oncogene addiction⁶. 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^{7, 8, 9, 10}. 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 cancers¹¹, 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.

1. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
2. Department of Radiation Oncology,
3. Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, Massachusetts 02129, USA, and Harvard Medical School, Boston, Massachusetts 02115, USA
4. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
5. These authors contributed equally to this work.

Correspondence to: Tyler Jacks^1,4 Correspondence and requests for materials should be addressed to T.J. (Email: tjacks@mit.edu).

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