Omega-3 Free Fatty Acids Inhibit Tamoxifen-induced MCF-7 Cell Apoptosis

Breast cancer is the most prevalent invasive cancer in women, and ranks as the second cause of cancer-related death worldwide. It is well established that antiestrogen therapy significantly suppresses the progression of estrogen receptor alpha(ERα)-positive breast cancer, and contributes to the reduction of breast cancer mortality[1]. Tamoxifen is a typical antiestrogen drug, administered as first-line treatment for both early and advanced breast cancer patients[2, 3]. However, approximately 50% of ERα-positive breast cancer patients develop tamoxifen resistance in clinical treatment, leading to treatment failure and cancer death[1, 4]. Previous studies have demonstrated that high expression of mitogen-activated protein kinase(MAPK) and AKT contributes to antiestrogen resistance[5-7].Researches in the field of lipid nutrition have highlighted the potential beneficial impacts of omega-3 polyunsaturated fatty acids(ω-3 PUFAs) on the prevention of cancers, such as the carcinogenesis of breast, prostate, colon, and kidney tissues[8-13]. Eicosapentaenoic acid(EPA) and docosahexaenoic acid(DHA) modulate breast carcinogenesis through activation of the apoptotic pathway and estrogen metabolism[14-17]. Alpha linolenic acid(ALA) is also known to have a protective effect on breast cancer[18].Whether ω-3 fatty acids interfere with the treatment efficacy of TAM in breast tumors and the molecular mechanisms involved remain to be further investigated. In the present study, we explore the effects of the individual and combined administration of Tamoxifen and ω-3FFA(EPA, DHA and ALA) on ER-positive breast cancer cells. Consistent with the results previously reported, ω-3FFA and TAM not only inhibit MCF-7 cell growth, but also induce cell apoptosis. Strikingly, we found that ω-3FFAs attenuated tamoxifen efficacy and induced tamoxifen resistance in MCF-7 cells. Moreover, ω-3FFA and tamoxifen significantly increased ERK1/2 and AKT phosphorylation levels in a dose and time dependent manner. Compared to ω-3FFA, combination of tamoxifen with ω-3FFA significantly increased ERK1/2 and AKT phosphorylation levels. These results indicate that that ω-3 free fatty acids attenuated tamoxifen effects by promoting ERK1/2 and AKT activation.Despite being safe and well-tolerated in health, side effects of fish oil still need to be considered. Of note, our results indicate that ω-3FFA attenuates tamoxifen-induced apoptosis in MCF-7 cells, suggesting ω-3FFA may present an unwanted drugedrug interaction in the prevention of tamoxifen for breast cancer risk. Elucidating the effect ofω-3FFA on tamoxifen signaling in cell apoptosis may provide novel therapeutic target for improving treatment of breast cancer patients.