The omega-3 polyunsaturated fatty acid (n-3 PUFA), α-linolenic acid (ALA), and its metabolites, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), independently reduce the growth of breast cancer cells in vitro, but the mechanisms, which may involve microRNA (miRNA), are still unclear. The expression of the oncomiR, miR-21, is reduced by DHA treatment, but the effects of ALA on miR-21, alone or combined with EPA and DHA under physiologically relevant concentrations, have not been investigated. The effects of ALA alone and +/−EPA and DHA at the blood molar ratios seen in either humans (1.0:1.0:2.5, ALA:EPA:DHA) or mice (1.0:0.4:3.1, ALA:EPA:DHA) post flaxseed oil consumption (containing ALA) were assessed in vitro in MCF-7 breast cancer cells. Cell viability and the expression of miR-21 and its molecular target, phosphatase and tension homolog (PTEN, gene and protein), at different time points, were examined. At 1, 3, 48 and 96 h ALA alone and 24 h animal ratio treatments significantly reduced MCF-7 cell viability, while 1 and 3 h ALA alone and human and animal ratio treatments all significantly reduced miR-21 expression, and 24 h animal ratio treatment reduced miR-21 expression; these effects were not associated with changes in PTEN gene or protein expressions. We showed for the first time that ALA alone or combined with EPA and DHA at levels seen in human and animal blood post-ALA consumption can significantly reduce cell viability and modulate miR-21 expression in a time- and concentration-dependent manner, with the animal ratio containing higher DHA having a greater effect. The time dependency of miR-21 effects suggests the significance of considering time as a variable in miRNA studies, particularly of miR-21.

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