These authors contributed equally to this work.
p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans
Article first published online: 8 JUN 2012
Copyright © 2012 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 4, Issue 8, pages 808–824, August 2012
How to Cite
Wild, P. J., Ikenberg, K., Fuchs, T. J., Rechsteiner, M., Georgiev, S., Fankhauser, N., Noske, A., Roessle, M., Caduff, R., Dellas, A., Fink, D., Moch, H., Krek, W. and Frew, I. J. (2012), p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans. EMBO Mol Med, 4: 808–824. doi: 10.1002/emmm.201101063
- Issue published online: 3 AUG 2012
- Article first published online: 8 JUN 2012
- Manuscript Accepted: 23 APR 2012
- Manuscript Revised: 20 APR 2012
- Manuscript Received: 8 NOV 2011
- Funded Access
- clear cell;
- endometrial carcinoma;
- mouse model;
Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.