Identification of a Molecular Signature Underlying Inhibition of Mammary Carcinoma Growth by Dietary N-3 Fatty Acids

Abstract

An increased ratio of dietary n-3 relative to n-6 fatty acids has been shown to inhibit the development of mammary cancer in animal models. However, the molecular mechanisms by which n-3 fatty acids affect tumor growth remain unknown. Here, we investigated the effects of varying dietary ratios of n-3:n-6 fatty acids on cell signaling in a rat model of chemically induced mammary carcinoma. Cell proliferation was reduced by 60% in carcinomas from the high n-3:n-6 treatment group compared with the low n-3:n-6 treatment group. These changes were associated with decreased cyclin-D1 and phospho-retinoblastoma protein expression and increased levels of cyclin-dependent kinase inhibitors, CIP1 (p21) and KIP1 (p27). In addition, the apoptotic index was increased in carcinomas from the high n-3:n-6 group and was associated with elevated apoptotic protease-activating factor 1 and a higher ratio of Bax/Bcl-2. Interestingly, changes in protein expression were consistent with reduced inflammation and suppressed mTOR activity, and the molecular signature associated with high n-3:n-6 treatment revealed changes in PPARg activation and suppression of lipid synthesis. Together, our findings indicate that the molecular effects of high dietary n-3 to n-6 ratios are heterogeneous in nature but point to consistent changes in lipid metabolism pathways, which may serve as potential therapeutic targets for cancer prevention and control. This study identifies the pathways modulated by dietary fatty acid ratios in a rat model of breast cancer, with implications for cancer prevention. Cancer Res; 72(15); 3795-806. Ó2012 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

“…For example, we showed that n-3:n-6 ratios of 10:1 and 25:1 upregulated Fetuin B. Fetuin B, a glycoprotein of the fetuin family, has been shown to be involved in fatty acid metabolism in human liver cell lines as supported by the observation that pACC and pAMPK were downregulated in fetuin B knockdown cells (20). Therefore, the upregulation of fetuin by high n-3:n-6 fatty acid ratios may provide a mechanism for the induction of pACC and pAMPK by high n-3:n-6 ratios as recently reported (12).…”

“…In a recent study, we showed (12) that the mechanism that can account for the chemopreventive activity of the high ratio of n-3:n-6 (25:1) against the development of mammary cancer is due to the inhibition of cell proliferation and more so the induction of apoptosis in the adenocarcinomas. In this previous report (12) we showed that in the target tissue (mammary adenocarcinomas) from the same animals from which plasma samples were collected using Western blot analysis changes in proteins involved in apoptosis, transcription regulation, growth factor regulation, and lipid metabolism were consistent with cancer prevention. Taken together, the results of this report (plasma proteins) and those of our previous study (ref.…”

“…As compared to control rats treated with MNU and fed a diet containing n-3:n-6 ratio of 1:1, tumor incidence was significantly decreased by 12%, 21%, and 72% in rats treated with MNU, but fed 10:1 n-3:n-6, 25:1 n-3:n-6, and 25:1 n-3:n-6 plus Tamoxifen, respectively (4,12). Tumor multiplicity was also decreased by 26%, 30%, and 80% in the rats fed 10:1 n-3:n-6, 25:1 n-3:n-6, and 25:1 n-3:n-6 plus Tamoxifen, respectively.…”

“…We found that high ratios of n-3:n-6 fatty acids with and without Tamoxifen affected plasma levels of proteins involved in cancer and lipid metabolism. It is proposed that n-3:n-6 fatty acid ratios influence the synthesis of lipids which is correlated to mammary tumor growth in MNUtreated rats (12). For example, we showed that n-3:n-6 ratios of 10:1 and 25:1 upregulated Fetuin B. Fetuin B, a glycoprotein of the fetuin family, has been shown to be involved in fatty acid metabolism in human liver cell lines as supported by the observation that pACC and pAMPK were downregulated in fetuin B knockdown cells (20).…”

Omega-3 and Omega-6 Fatty Acids in Blood and Breast Tissue of High-Risk Women and Association with Atypical Cytomorphology

“…A review of 81 rodent studies concluded that dietary omega-6 fatty acids dose-dependently accelerate mammary tumorigenesis (11). Conversely, dietary EPA and DHA prevent mammary tumor development in animals (12)(13)(14)(15). The effect of omega-3 and omega-6 intake on breast cancer risk in humans has not been determined.…”