Mammary Gland Density Predicts the Cancer Inhibitory Activity of the N-3 to N-6 Ratio of Dietary Fat

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 ¼ À0.477, P ¼ 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 ¼ 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 ¼ 0.004) and was predictive of the changes in mammary gland density (r ¼ 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. Cancer Prev Res; 4(10); 1675-85. Ó2011 AACR.

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

“…The plasma evaluated in this study was obtained from rats used in a recently published study (4), testing the chemopreventive effects of different n-3:n-6 ratios individually and in combination with Tamoxifen. Briefly, female Sprague Dawley rats were injected intraperitoneally at 21 days of age with 50 mg of MNU/kg body weight as previously described (4).…”

“…It has been postulated that the risk of breast cancer can be influenced by certain dietary components such as the amount and type of dietary fats ingested (3)(4)(5)(6)(7). Among the fatty acids, omega-3 (n-3) and omega-6 (n-6) fatty acids have been suggested to decrease and increase breast cancer risk, respectively.…”

“…Furthermore, several chemoprevention studies in animal models used diets that were high in the percent of dietary calories provided from fat which are not consistent with the U.S. Dietary Guidelines (8). Because both issues (% calories from fat and n-3:n-6 ratio) are problematic from the translational perspectives, this stimulated our team (4) to formulate a series of experiments testing the chemopreventive efficacy of purified diets modified to reflect levels of dietary fat which are currently recommended in the U.S. Dietary Guidelines (8). In addition, within the polyunsaturated fatty acids the ratio of n-3: n-6 fatty acids was varied from 25:1 to 1:25 to provide a robust evaluation of the role of this ratio in affecting the postinitiation phase of 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in the rat (4).…”

“…Because both issues (% calories from fat and n-3:n-6 ratio) are problematic from the translational perspectives, this stimulated our team (4) to formulate a series of experiments testing the chemopreventive efficacy of purified diets modified to reflect levels of dietary fat which are currently recommended in the U.S. Dietary Guidelines (8). In addition, within the polyunsaturated fatty acids the ratio of n-3: n-6 fatty acids was varied from 25:1 to 1:25 to provide a robust evaluation of the role of this ratio in affecting the postinitiation phase of 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in the rat (4). Our laboratories were the first to show that the combination of n-3 fatty acids with Tamoxifen was a more effective chemopreventive regimen than the individual interventions (4,9).…”

“…In addition, within the polyunsaturated fatty acids the ratio of n-3: n-6 fatty acids was varied from 25:1 to 1:25 to provide a robust evaluation of the role of this ratio in affecting the postinitiation phase of 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in the rat (4). Our laboratories were the first to show that the combination of n-3 fatty acids with Tamoxifen was a more effective chemopreventive regimen than the individual interventions (4,9). Specifically, we observed that high n-3:n-6 ratios (10:1 and 25:1) were able to suppress carcinogenesis in Tamoxifentreated animals, thus suggesting that they are able to inhibit the development of hormone-resistant tumors.…”