Tumorigenesis in the Multiple Intestinal Neoplasia Mouse: Redundancy of Negative Regulators and Specificity of Modifiers

The interaction between mutations in the tumor-suppressor genes Apc and p53 was studied in congenic mouse strains to minimize the influence of polymorphic modifiers. The multiplicity and invasiveness of intestinal adenomas of ApcMin//+(Min) mice was enhanced by deficiency for p53. In addition, the o...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 97; no. 7; pp. 3461 - 3466
Main Authors Halberg, Richard B., Katzung, Darren S., Hoff, Peter D., Moser, Amy R., Cole, Carolyn E., Lubet, Ronald A., Donehower, Lawrence A., Jacoby, Russell F., Dove, William F.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences of the United States of America 28.03.2000
National Acad Sciences
National Academy of Sciences
The National Academy of Sciences
Subjects
Adenoma
Adenoma - genetics
Adenoma - pathology
Aggressive fibromatosis
Alleles
Animals
Apc gene
Biological Sciences
difluoromethylornithine
Drug interactions
Eflornithine - pharmacology
Female
Fibroma
Fibromatosis, Aggressive - genetics
Genes, APC
Genes, p53
Genotypes
Intestinal Neoplasms - genetics
Intestinal Neoplasms - pathology
Large intestine
Male
Mice
Mice, Inbred C57BL
Mom1 gene
Mutation
Neoplasia
Neoplasms, Multiple Primary - genetics
Neoplasms, Multiple Primary - pathology
p53 gene
piroxicam
Piroxicam - pharmacology
Regulator genes
Rodents
Small intestine
Tumors
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Summary:The interaction between mutations in the tumor-suppressor genes Apc and p53 was studied in congenic mouse strains to minimize the influence of polymorphic modifiers. The multiplicity and invasiveness of intestinal adenomas of ApcMin//+(Min) mice was enhanced by deficiency for p53. In addition, the occurrence of desmoid fibromas was strongly enhanced by p53 deficiency. The genetic modifier Mom1 and the pharmacological agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function. Mom1 showed no influence on the development of desmoid fibromas, whereas the combination of piroxicam and difluoromethylornithine exerted a moderate effect. The ensemble of tumor suppressors and modifiers of a neoplastic process can be usefully analyzed in respect to tissue specificity and synergy.
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Contributed by William F. Dove
To whom reprint requests should be addressed. E-mail: dove@oncology.wisc.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.050585597