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Carcinogenesis Advance Access published online on May 11, 2005
Carcinogenesis, doi:10.1093/carcin/bgi118
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received December 9, 2004
Revised March 23, 2005
Accepted May 3, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Opposing effects of prepubertal low and high fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis

Susan E. Olivo 1 and Leena Hilakivi-Clarke 1*

1 Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd NW, Washington, DC, USA

* To whom correspondence should be addressed.
Leena Hilakivi-Clarke, E-mail: clarkel{at}georgetown.edu


  Abstract

To determine whether dietary fat intake during childhood affects later risk of developing breast cancer, we fed prepubertal rats between postnatal days 5 and 25 a low (16% energy) or high fat (39% energy) diet composed mainly of n-6 or n-3 polyunsaturated fatty acids (PUFAs) originating either from corn oil or menhaden oil, respectively, at the ratios of 16-17:1 (n-6 PUFA diets) or 2-3:1 (n-3 PUFA diets). We also examined whether changes in risk are associated with perturbations in biological processes previously linked to fatty acid intake and breast cancer. Mammary tumorigenesis was induced by treating 50-day-old rats with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). When compared with the reference low fat n-6 PUFA diet, prepubertal exposure to the low fat n-3 PUFA diet decreased, while a high fat n-3 PUFA diet increased mammary tumor incidence; the high fat n-6 PUFA diet had no effect. Both the low and high fat n-3 PUFA diets induced mammary epithelial differentiation by reducing the number of terminal end buds (TEBs) and increasing the presence of lobulo-alveolar structures. They also increased lipid peroxidation and reduced COX-2 activity. Prepubertal exposure to the low fat n-3 PUFA diet increased apoptosis, determined using TUNEL assay, and reduced cell proliferation, determined using PCNA staining. In marked contrast, prepubertal exposure to the high fat n-3 PUFA diet induced cell proliferation and inhibited apoptosis in the TEBs and lobular structures. The latter is consistent with the finding that pAkt, a survival factor that inhibits apoptosis, was elevated in their mammary glands. In summary, although prepubertal exposure to a low fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast cancer risk.

Keywords: breast cancer; diet during puberty; polyunsaturated fatty acids; apoptosis.
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