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Muir-Torre-like syndrome in Fhit-deficient mice
Abstract:
To investigate the role of the Fhit gene in carcinogen induction of neoplasia, we have inactivated one Fhit allele in mouse embryonic stem cells and produced (129/SvJ x C57BL/6J) F(1) mice with a Fhit allele inactivated (+/-). Fhit +/+ and +/- mice were treated intragastrically with nitrosomethylbenzylamine and observed for 10 wk posttreatment. A total of 25% of the +/+ mice developed adenoma or papilloma of the forestomach, whereas 100% of the +/- mice developed multiple tumors that were a mixture of adenomas, squamous papillomas, invasive carcinomas of the forestomach, as well as tumors of sebaceous glands. The visceral and sebaceous tumors, which lacked Fhit protein, were similar to those characteristic of Muir-Torre familial cancer syndrome.
Insights
Inactivating one Fhit gene allele significantly increases susceptibility to carcinogen-induced tumors in mice. Mice lacking one Fhit allele developed forestomach and sebaceous gland tumors, unlike their normal counterparts.
Area of Science:
- Oncology
- Genetics
- Carcinogenesis
Background:
- The Fragile Histidine Triad (Fhit) gene plays a crucial role in tumor suppression.
- Understanding Fhit's function in carcinogen-induced neoplasia is vital for cancer research.
Purpose of the Study:
- To investigate the role of the Fhit gene in the development of cancer when one allele is inactivated.
- To determine the impact of Fhit gene status on susceptibility to carcinogen-induced tumors.
Main Methods:
- Mouse embryonic stem cells with one inactivated Fhit allele were generated.
- (129/SvJ x C57BL/6J) F(1) mice with a Fhit allele inactivated (+/-) were produced and treated with nitrosomethylbenzylamine.
- Tumor development in Fhit +/+ and +/- mice was monitored over 10 weeks.
Main Results:
- 25% of wild-type (Fhit +/+) mice developed forestomach tumors.
- 100% of Fhit +/- mice developed multiple tumors, including forestomach adenomas, squamous papillomas, invasive carcinomas, and sebaceous gland tumors.
- The observed tumors in Fhit +/- mice, which lacked Fhit protein, resembled those seen in Muir-Torre syndrome.
Conclusions:
- Inactivation of one Fhit allele dramatically increases susceptibility to carcinogen-induced forestomach and sebaceous gland tumors.
- Fhit deficiency is strongly linked to the development of specific tumor types, suggesting its critical role in preventing neoplasia.
- These findings highlight the Fhit gene's importance in cancer suppression and its potential connection to familial cancer syndromes.