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Carcinogenesis Advance Access published online on May 11, 2005
Carcinogenesis, doi:10.1093/carcin/bgi117
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received February 15, 2005
Revised April 25, 2005
Accepted April 29, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Effects of dietary folate on the development and progression of mammary tumors in rats

Joanne Kotsopoulos 1, Alan Medline 2, Richard Renlund 3, Kyoung-Jin Sohn 4, Rochelle Martin 5, Stephen W. Hwang 6, Suying Lu 1, Michael C. Archer 1, and Young-In Kim 7*

1 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
3 Division of Comparative Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
5 Inner City Health Research Unit, St. Michael's Hospital, Toronto, Ontario, Canada
6 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Inner City Health Research Unit, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
7 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada

* To whom correspondence should be addressed.
Young-In Kim, E-mail: youngin.kim{at}utoronto.ca


  Abstract

Epidemiologic studies have suggested that dietary intake and blood levels of folate may be inversely related to the risk of breast cancer. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. Recent evidence has also raised a concern that folate supplementation may promote carcinogenesis if provided after neoplastic foci are established in the target organ. This study investigated the effect of dietary folate deficiency and supplementation on the development and progression of mammary tumors in the N-methyl-N-nitrosourea (MNU) rat model. Weanling, female Sprague-Dawley rats were fed diets containing either 0, 2 (control) or 8 mg folic acid/kg diet during the initiation or promotion phase of MNU-induced mammary tumorigenesis. At necropsy, all macroscopic mammary tumors were identified and histologically confirmed. Dietary folate deficiency and supplementation provided during the initiation phase did not significantly modulate the development of mammary tumors. In contrast, dietary folate deficiency provided during the promotion phase significantly inhibited the rate of appearance, incidence, mean volume and weight of adenocarcinomas compared with the control and supplemental diets. Folate supplementation provided during the promotion phase did not significantly modulate mammary tumorigenesis compared with the control group. These data indicate that moderate folate deficiency inhibits, whereas dietary folate supplementation at 4x the basal dietary requirement does not promote, the progression of MNU-induced mammary neoplastic foci in this rat model. However, the limitations associated with the route and dose of MNU administration preclude a definitive conclusion concerning the effect of folate status on the initiation of MNU-induced mammary tumorigenesis.

Keywords: Folate; breast cancer; N-methyl-N-nitrosourea; DNA methylation; rats.
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