p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma

Doyle, B., Morton, J. P. , Delaney, D. W., Ridgway, R. A., Wilkins, J. A. and Sansom, O. J. (2010) p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. Journal of Pathology, 222(2), pp. 129-137. (doi: 10.1002/path.2748) (PMID:20662002)

Abstract

Pleomorphic rhabdomyosarcoma is the most common variant of this tumour in adults and has a very poor outcome. Two genes which are known to play a role in rhabdomyosarcoma development are KRas and p53. In the majority of human tumours, p53 abnormalities are point mutations that result in the expression of a mutant form of the protein. It is now hypothesized that these mutant forms of p53 may be playing an oncogenic role, over and above simple loss of the wild‐type function. In this study, we use Cre‐LoxP technology to develop a novel mouse model of rhabdomyosarcoma, crossing mice expressing a common KRas mutation (G12V) with mice that either lose p53 expression or express a mutant form of p53. We use this model to explore the different effects of p53 loss and mutation in the setting of an activating KRas mutation. We found that either complete loss of p53 (p53equation image) or the expression of one mutant p53 allele with concomitant loss of the second allele (p53equation image) resulted in the rapid development of rhabdomyosarcoma in 15/16 and 19/19 mice, respectively. In contrast, there was a marked difference between mice which lose a single copy of p53 (p53equation image) and mice expressing a single copy of mutant p53 (p53equation image). Fourteen out of 16 p53equation image mice developed rhabdomyosarcoma, compared with two out of 31 p53equation image mice. As a consequence of this, p53equation image mice had a median lifespan nearly double that of the p53equation image mice. To underline the enhanced effect of p53 mutation in tumour progression, metastases were seen only in those mice which expressed the mutant form. These data demonstrate that mutant p53 can co‐operate with activated, mutant KRas to influence tumourigenesis and metastatic potential, over and above simple loss of normal protein function.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Ridgway, Dr Rachel and Sansom, Professor Owen
• Authors: Doyle, B., Morton, J. P., Delaney, D. W., Ridgway, R. A., Wilkins, J. A., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Pathology
• Publisher: Wiley
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 17 June 2010