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 PPARγ 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.
Highlights
Previous work identified dietary concentrations of n-3 relative to n-6 fatty acids that inhibited chemically induced mammary carcinogenesis [1]
Because an understanding of the mechanisms by which n-3 fatty acids affect the balance between cell proliferation and cell death is important to assess their potential value in both cancer prevention and cancer control [2], this investigation focused on identifying candidate pathways by which a high dietary ratio of n-3:n-6 affected tumor size homeostasis, that is, the balance between cell proliferation and cell death [3]
Primary antibodies used in this study were anti-cyclin-D1, anti-p27Kip1, and anti-Ki-67 from Thermo Fisher Scientific; anti-Bax and antiBcl-2 from BD Biosciences (anti-GADD153, Hypoxia-inducible factor (Hif)-1a, and GPR120 from Novus Biologicals, anti-pIRS/pIRS, anti-PARPs, www.aacrjournals.org anti-pRB/RB, anti-Apaf-1, anti-pFOXO1&3/FOXO1&3, antiNFkB-p65, anti-SIRT-1, anti-fatty acid synthase (FASN), anti-PI3Kp110, anti-pAMPK/ AMPactivated protein kinase (AMPK), anti-pACC/ACC, anti-pAkt/Akt, anti-pmTOR/mTOR, anti-pP70S6/P70S6, anti-p4E-BP1/4E-BP1, anti-p-Raptor/Raptor, anti-p-PRAS40/PRAS40, anti-rabbit immunoglobulin-horseradish peroxidase (HRP)-conjugated secondary antibody, and LumiGLO reagent with peroxide were purchased from Cell Signaling Technology; anti-IGFR-1, anti-p21Cip1, anti-PPARa, b, g, anti-HMGCR, anti-SREBP-1, and anti-mouse immunoglobulin-HRP-conjugated secondary antibody were from Santa Cruz; and mouse anti-b-actin primary antibody was obtained from Sigma-Aldrich
Summary
Previous work identified dietary concentrations of n-3 relative to n-6 fatty acids that inhibited chemically induced mammary carcinogenesis [1]. Of the various aspects of the carcinogenic response inhibited, the effect of high n-3:n-6 was greatest on tumor burden. Because an understanding of the mechanisms by which n-3 fatty acids affect the balance between cell proliferation and cell death is important to assess their potential value in both cancer prevention and cancer control [2], this investigation focused on identifying candidate pathways by which a high dietary ratio of n-3:n-6 affected tumor size homeostasis, that is, the balance between cell proliferation and cell death [3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). While there are Authors' Affiliations: 1Cancer Prevention Laboratory, Colorado State University, Fort Collins, Colorado; and 2Penn State University College of Medicine, Hershey, Pennsylvania
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