p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans
Abstract
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.
Additional Information
© 2012 EMBO Molecular Medicine. Received November 08, 2011. Revised April 20, 2012. Accepted April 23, 2012. Article first published online: 8 Jun 2012. We thank Silvia Behnke, Martina Storz, Susanne Dettwiler, Annette Bohnert, Sonja Brun-Schmid, Adriana von Teichman and Marcel Glönkler for excellent technical assistance and Simone Holdermann for critical reading of the manuscript. This work was supported by an SNF Förderungsprofessur grant to IJF and a Baugarten Foundation grant to PJW. Author contributions IJF, PJW and WK designed the experiments; IJF, PJW, KI, TJF, SG, MR and NF conducted and analysed the experiments; PJW, AN, MR, RC and HM conducted the histopathological analyses; AD, DF and HM generated the TMAs; IJF and PJW wrote the manuscript with the assistance of all authors. The authors declare that they have no conflict of interest.Attached Files
Published - 808_ftp.pdf
Supplemental Material - emmm_201101063_sm_Review_Process_File.pdf
Supplemental Material - emmm_201101063_sm_suppdata.pdf
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Additional details
- Eprint ID
- 34087
- Resolver ID
- CaltechAUTHORS:20120914-100811591
- SNF Förderungsprofessur
- Baugarten Foundation
- Created
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2012-09-14Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field