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Development of rhabdomyosarcoma in HER-2/neu transgenic p53 mutant mice
Patrizia Nanni1, Giordano Nicoletti, Carla De Giovanni
1Cancer Research Section, Department of Experimental Pathology, University of Bologna, I-40126 Bologna.
Abstract:
Rhabdomyosarcomas derive from the skeletal muscle lineage and harbor a variety of genetic and molecular lesions. However, it is not clear which molecular alterations have a pathogenetic role. We show that activation of the HER-2/neu oncogene coupled with inactivation of the oncosuppressor gene p53 causes rhabdomyosarcoma in mice. At the age of 11-21 weeks, all male mice carrying both genetic lesions developed embryonal rhabdomyosarcomas expressing desmin, myosin, and insulin-like growth factor-II, in the genitourinary tract. Our findings led to the hypothesis that the interaction between HER family genes and the p53 pathway might be involved in the origin of human rhabdomyosarcoma.
Insights
Activation of the HER-2/neu oncogene and inactivation of the p53 tumor suppressor gene together cause rhabdomyosarcoma in mice. This finding suggests a potential link between these genetic alterations and human rhabdomyosarcoma development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Rhabdomyosarcomas originate from skeletal muscle cells and present diverse genetic mutations.
- The specific molecular drivers of rhabdomyosarcoma pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the pathogenetic role of specific molecular alterations in rhabdomyosarcoma development.
- To determine if combined activation of HER-2/neu and inactivation of p53 can induce rhabdomyosarcoma.
Main Methods:
- Utilized a mouse model to study the combined effects of genetic lesions.
- Analyzed tumor development, histology, and protein expression in affected mice.
Main Results:
- Mice with both activated HER-2/neu and inactivated p53 developed embryonal rhabdomyosarcomas.
- Tumors were observed in the genitourinary tract and expressed key markers like desmin, myosin, and insulin-like growth factor-II.
- Onset of tumors occurred between 11-21 weeks of age in male mice.
Conclusions:
- The co-occurrence of HER-2/neu activation and p53 inactivation is sufficient to cause rhabdomyosarcoma in mice.
- These findings propose a potential pathogenetic mechanism involving the interaction between HER family signaling and the p53 pathway in human rhabdomyosarcoma.