Muir–Torre-like syndrome in Fhit-deficient mice

Muir–Torre-like syndrome in Fhit-deficient mice

Departments of ^*Microbiology and Immunology, ^§Pathology, Anatomy, and Cell Biology, and ^‡Medicine and Christiana Care Health Systems, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107

Contributed by Carlo M. Croce

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 × C57BL/6J) F₁ 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.

Footnotes

↵ † L.Y.Y.F. and V.F. contributed equally to this work.
↵ ¶ To whom reprint requests should be addressed. E-mail: huebner{at}lac.jci.tju.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.080063497.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.080063497
Abbreviations:

NMBA,

N-nitrosomethylbenzylamine;

H&E,

hematoxylin and eosin;

MTS,

Muir–Torre syndrome;

MSI,

microsatellite instability;

ES,

embryonic stem;

HNPCC,

hereditary nonpolyposis colorectal cancer;

GST,

glutathione S-transferase