Muir-torre-like syndrome in Fhit deficient mice
The invention provides nonhuman transgenic animals with a disrupted FHIT gene. The invention further provides transgenic mice in which one or both Fhit alleles have been inactivated. Preferably, the Fhit-deficient mice develop multiple tumors of both visceral and sebaceous origin, similar to those of Muir-Torre familial cancer syndrome. The present invention further relates to the generation of these transgenic mice and their use as model systems to study the effects of carcinogenic agents in promoting clonal expansion of neoplastic cells in cancers, preferably gastrointestinal cancers of which Muir-Torre syndrome is a subset. The invention further relates to testing therapeutic agents for their efficacy in the prevention and treatment of cancer, preferably gastrointestinal cancer.
1. A transgenic mouse the genome of which contains a disruption in the mouse FHIT gene, wherein said disruption comprises a termination codon in exon 5 of the FHIT gene, and wherein said mouse (a) has increased susceptibility to visceral and sebaceous tumors relative to FHIT +/+ mice, or (b) displays increased tumor formation upon being exposed to N-nitrosomethylbenzlamine relative to FHIT +/+ mice that have been exposed to N-nitrosomethylbenzlamine.
2. The transgenic mouse of claim 1 , wherein said disruption of the FHIT gene is homozygous.
3. The transgenic mouse of claim 1 , wherein said disruption of the PHIT gene is heterozygous.
4. The transgenic mouse of claim 2 or 3 , said mouse having increased susceptibility to visceral and sebaceous tumors relative to FHIT +/+ mice.
5. The transgenic mouse of claim 2 or 3 , wherein said mouse displays increased tumor formation upon being exposed to N-nitrosomethylbenzlamine relative to FHIT +/+ mice.
6. A transgenic mouse, wherein said mouse is chimeric for a disruption in the mouse FHIT gene, wherein said disruption comprises a termination codon in exon 5 of the FHIT gene, and wherein FHIT +/− progeny of said mouse (a) have increased susceptibility to visceral and sebaceous tumors relative to FHIT +/+ mice, or (b) display increased tumor formation upon being exposed to N-nitrosomethylbenzlamine relative to FHIT +/+ mice that have been exposed to N-nitrosomethylbenzlamine.
7. The transgenic mouse of claim 6 , wherein said disruption of the FHIT gene is in both germline and somatic cells.
8. A method of testing carcinogenicity of a molecule, comprising:
(a) administering said molecule to the transgenic mouse of claim 1 , 7 , 2 or 3 ; and
(b) comparing the rate of tumor formation in said transgenic mouse with a control mouse of the same genotype to which the molecule is not administered;
wherein an increased rate of tumor formation in the transgenic mouse following administration of the test molecule, as compared to the rate of tumor formation in the control mouse, is indicative that the molecule is carcinogen.
9. A method of testing the therapeutic efficacy of a molecule in treating or preventing cancer comprising:
(a) administering said molecule to the transgenic mouse of claim 1 , 7 , 2 or 3 ; and
(b) comparing the rate of tumor formation in said transgenic mouse with a control mouse of the same genotype to which the molecule is not administered;
wherein a reduced rate of tumor formation in the transgenic mouse following administration of the test molecule, as compared to ihe rate of tumor formation in the control mouse, is indicative that the molecule has therapeutic or prophylactic value for cancer.
10. The method of claim 9 , wherein the cancer is a gastrointestinal cancer.
11. The method of claim 9 , where in the cancer is Muir-Torre Syndrome-related cancer.
12. The method of claim 9 , wherein the cancer is hereditary non-polyposis colorectal cancer.