17β‐Estradiol Increases Liver and Serum Docosahexaenoic Acid in Mice Fed Varying Levels of α‐Linolenic Acid

Abstract

Docosahexaenoic acid (DHA) is considered to be important for cardiac and brain function, and 17β-estradiol (E2) appears to increase the conversion of α-linolenic acid (ALA) into DHA. However, the effect of varying ALA intake on the positive effect of E2 on DHA synthesis is not known. Therefore, the objective of this study was to investigate the effects of E2 supplementation on tissue and serum fatty acids in mice fed a low-ALA corn oil-based diet (CO, providing 0.6 % fatty acids as ALA) or a high ALA flaxseed meal-based diet (FS, providing 11.2 % ALA). Ovariectomized mice were implanted with a slow-release E2 pellet at 3 weeks of age and half the mice had the pellet removed at 7 weeks of age. Mice were then randomized onto either the CO or FS diet. After 4 weeks, the DHA concentration was measured in serum, liver and brain. A significant main effect of E2 was found for liver and serum DHA, corresponding to 25 and 15 % higher DHA in livers of CO and FS rats, respectively, and 19 and 13 % in serum of CO and FS rats, respectively, compared to unsupplemented mice. There was no effect of E2 on brain DHA. E2 results in higher DHA in serum and liver, at both levels of dietary ALA investigated presently, suggesting that higher ALA intake may result in higher DHA in individuals with higher E2 status.

α-Linolenic Acid Reduces Growth of Both Triple Negative and Luminal Breast Cancer Cells in High and Low Estrogen Environments

“…Many assume that ALA has less potent effects than its longer chain EPA and DHA metabolites (49), but our study shows that ALA at lower doses (50 mM) significantly reduces the growth not only of MCF-7 and MDA-MB-231 cell lines, but also the HER2 overexpressing BT-474 and TNBC MDA-MB-468 cell lines, both with and without E2. As previously indicated, the 50 mM ALA that caused growth reduction of BC cells is physiologically relevant, with serum ALA concentrations in animal and clinical studies exceeding this with intakes of 4% flaxseed oil and 6 g/day ALA diets, respectively (34)(35)(36)(37). A comparison of the cell lines showed that MDA-MB-231 cells have significantly larger reductions in growth from ALA treatment (75 mM) compared to the luminal A MCF-7 cells.…”

“…Medium was switched to treatment medium with 0, 50, 75, 100, 125, 150, or 200 mM ALA § 1 nM E2, 3 wells per treatment condition. These concentrations were selected because they are physiological, based on in vivo mouse and rabbit plasma concentrations achieved after ALA supplementation ranging from 98 to 600 mM (34,35), and human plasma ALA concentrations over 200 mM with diet supplementation of 6 g ALA/day (36,37). The above levels have also been used in many previous in vitro research (5)(6)(7)(8)(38)(39)(40)(41)(42).…”

Growth and gene expression differ over time in alpha-linolenic acid treated breast cancer cells

“…Control medium contained no ALA but with the same concentration of FBS and E2. A concentration of 75 μM ALA was selected as it reduces growth by at least 50% in these four BC cell lines after 96 h treatment time [49], and is physiologically relevant as in vivo studies in mice showed serum concentrations over 100 μM after feeding a 10% FS or 4% flaxseed oil diet [15,28] and human serum reached 197.5 μM with intake of a 6 g/day ALA diet [2]. Treatment medium contained E2 to ensure usual growth in estrogen dependent cell lines.…”

α-linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab, reduce HER2-overexpressing breast cancer cell growth but differentially regulate HER2 signaling pathways

“…Serum and tumor levels of ALA and long chain n-3 PUFAs EPA and DHA are significantly higher in mice fed 4 % FSO or 10 % FS diets compared to corn oil-based basal diets [ 7 , 11 , 12 , 14 ]. DHA and DHA-rich fish oil have demonstrated anticancer effects [ 15 – 20 ] and have also been shown to affect HER2 signaling [ 17 ] in models of HER2 overexpressing breast cancer.…”