Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele.
Altered patterns of the 5-cytosine methylation of genomic DNA are associated with the development of a wide range of human cancers. We have studied the mechanisms and genetic pathways by which a targeted heterozygous deficiency in the murine 5-cytosine DNA methyltransferase gene (Dnmt1(N/+)) diminishes intestinal tumorigenesis in C57BL/6-multiple intestinal neoplasia (Min)/+ mice. We found that Dnmt1(N/+) retards the net growth rate of intestinal adenomas and reduces tumor multiplicity by approximately 50%. This tumor resistance affects the entire intestinal tract and is independent of the status of modifier of Min 1 and p53, two loci that have been found to confer strong resistance to Min-induced neoplasia Interestingly, Dnmt/(N/+) and modifier of Min 1 resistance interact synergistically, together virtually eliminating tumor incidence. This finding may provide an insight into potential combinatorial therapeutic approaches for treating human colon cancer.
Cormier
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RT
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706, USA.
Dove
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WF
D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000367:Age Factors; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000502:physiology; D019175:DNA Methylation; D004261:DNA Replication / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D001973:Bromodeoxyuridine