Abstract
This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = -0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P < 0.001. Mammary carcinogenesis was inhibited in the absence or presence of tamoxifen (1 mg/kg diet) in a manner predicted by mammary gland density. Plasma n-3 fatty acid concentrations failed to increase above an n-3:n-6 ratio of 5:1, and changes in specific plasma n-3 or n-6 fatty acids were not predictive of mammary gland density or cancer inhibitory activity. A strong reciprocal effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P < 0.001) was observed indicating adipose tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P < 0.005). These findings indicate that (i) mammary gland density predicted the carcinogenic response, (ii) the n-3:n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation.
Highlights
The general perception exists that diets enriched in n-3 relative to n-6 fatty acids have a broad range of healthrelated benefits, a review of the literature reveals that the epidemiologic data in support of an inverse relationship between n-3 fatty acid consumption and breast cancer risk are mixed [1,2,3,4,5,6]
We report that mammary gland density predicted the carcinogenic response that the n-3: n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis and that signaling pathways regulated by insulin-like growth factor I (IGF-I) are potential targets for further mechanistic investigation
With increasing levels of n-3 fatty acids (n-3:n-6 ratio 1⁄4 1:1, 5:1, 10:1, and 25:1), mammary gland density was progressively reduced (r 1⁄4 À0.477, P 1⁄4 0.038) and the difference reached a magnitude of 25% in the screening assay at n-3:n-6 ratio of 25:1 versus 1:1 (Fig. 1A–C)
Summary
The general perception exists that diets enriched in n-3 relative to n-6 fatty acids have a broad range of healthrelated benefits, a review of the literature reveals that the epidemiologic data in support of an inverse relationship between n-3 fatty acid consumption and breast cancer risk are mixed [1,2,3,4,5,6]. One observation that emerged from the review of the preclinical evidence was that the majority of animal carcinogenesis experiments have been done using diets that were high in the percent of dietary calories provided from fat (40%–50%) and that few experiments varied the ratio of n-3 to n-6, despite the fact that considerable emphasis has been placed on this ratio in hypothesized mechanisms of action [1] Both issues are problematic from a translational perspective because recent clinical trials suggest that it is unusual for women at risk for breast cancer to exceed 35% of dietary calories from fat and that most women are likely to ingest n-3 fatty acids from a dietary supplement [19,20,21]. Within the polyunsaturated fatty acids, we sought to vary the ratio of n-3 to n-6 fatty acid from 25:1 to 1:25 to provide a robust evaluation of the role of this ratio in affecting the postinitiation phase of chemically induced mammary carcinogenesis
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