Combination of Antiestrogens and Omega-3 Fatty Acids for Breast Cancer Prevention

Figure 2

Cellular processes regulating transcription factors, insulin signaling, and lipid synthesis that are likely to account for the effects on cell proliferation and apoptosis in mammary carcinomas of rats fed high versus low (control) dietary ratio of n-3 : n-6 fatty acids. Diameter of red (decreased expression) and green arrows (increased expression) indicates magnitude of effect and font size of stated proteins indicates relative importance as determined by Orthogonal Projections to Latent Structures for Discriminant Analysis (OPLS-DA) (Refer to [21] for detailed description of the method). Peroxisome proliferator-activated receptor gamma (PPARγ) and to a lesser extent, G-coupled protein receptor 120 (GPR-120) attenuate inflammation via direct or indirect effects on nuclear factor kappa B (NFκB) and hypoxia-inducible factor-1α (HIF1α). PPARγ affects multiple targets in lipid metabolism including fatty acid synthase (FASN). In addition, high dietary n3 : n6 is accompanied by reduced activity of the mammalian target of rapamycin (mTOR) as reflected in the reduced phosphorylation of its downstream targets including 70-kDa ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which in turn exert effects on cell proliferation and cell survival. Mechanisms by which mTOR activity is downregulated include (1) downregulation of insulin growth factor 1 receptor (IGF-1R), phosphorylated insulin receptor substrate 1 (pIRS1), phosphoinositide 3-kinase (PI3K), phosphorylated Akt, phosphorylated Forkhead box O, and phosphorylated 40-kDa proline-rich protein (PRAS40); and (2) upregulation of phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) by increased adiponectin and decreased leptin, phosphorylated acetyl-CoA carboxylase (ACC), and phosphorylated regulatory associated protein of mTOR (Raptor). Decreased phosphorylated mTOR and increased pAMPK further attenuate fatty acids synthesis via reduction of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and of sterol regulatory element-binding protein 1 (SREBP1) that results in decrease of FASN. The overall consequence of these changes in cell signaling is a decrease in cell proliferation and an increase in cell death by apoptosis. Reproduced with permission from [21].