Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice

Lawrance, Andrea K.; Deng, Liyuan; Brody, Lawrence C.; Finnell, Richard H.; Shane, Barry; Rozen, Rima

doi:10.1016/j.jnutbio.2006.06.001

« Previous Next »The Journal of Nutritional Biochemistry
Volume 18, Issue 5 , Pages 305-312, May 2007

Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apc^min/+ mice

Andrea K. Lawrance
- Department of Human Genetics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Biology, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
Liyuan Deng
- Department of Human Genetics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Biology, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
Lawrence C. Brody
- Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD, USA
Richard H. Finnell
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA
Barry Shane
- Department of Nutritional Sciences, University of California, Berkeley, CA, USA
Rima Rozen
- Department of Human Genetics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Department of Biology, McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
- Corresponding author. Montreal Children's Hospital Research Institute, Montreal, Canada H3Z 2Z3. Tel.: +1 514 412 4358; fax: +1 514 412 4331.

Received 19 April 2006; received in revised form 14 June 2006; accepted 19 June 2006. published online 12 September 2006.

Abstract

Epidemiological studies indicate that adequate dietary folate is protective against colon cancer, although mechanisms remain largely elusive. We investigated the effects of genetic disruptions of folate transport and metabolism and of dietary folate deficiency in a mouse model of colon cancer, the Apc^min/+ mouse. Apc^min/+ mice with heterozygous knockout of the gene for reduced folate carrier 1 (Rfc1^+/−) developed significantly fewer adenomas compared to Rfc1^+/+Apc^min/+ mice [30.3±4.6 vs. 60.4±9.4 on a control diet (CD) and 42.6±4.4 vs. 55.8±7.6 on a folate-deficient diet, respectively]. Rfc1^+/−Apc^min/+ mice also carried a lower tumor load, an indicator of tumor size as well as of tumor number. In contrast, there were no differences in adenoma formation between Apc^min/+ mice carrying a knockout allele for methionine synthase (Mtr^+/−), an enzyme that catalyzes folate-dependent homocysteine remethylation, and Mtr^+/+Apc^min/+ mice. However, in both Mtr groups of mice, dietary folate deficiency significantly increased adenoma number (from 32.3±3.8 on a CD to 48.1±4.2 on a folate-deficient diet), increased plasma homocysteine, decreased global DNA methylation in preneoplastic intestines and increased apoptosis in tissues. There were no genotype-associated differences in these parameters in the Rfc1 group, suggesting that the protection conferred by Rfc1 deficiency is carried out through a different mechanism. In conclusion, genetic and nutritional disturbances in folate metabolism can have distinct influences on tumorigenesis in Apc^min/+ mice; altered levels of homocysteine, global DNA methylation and apoptosis may contribute mechanistically to dietary influence.