Docosahexaenoic acid induces proteasome-dependent degradation of estrogen receptor α and inhibits the downstream signaling target in MCF-7 breast cancer cells

About two thirds of breast cancers in women are hormone-dependent and require estrogen for growth, its effects being mainly mediated through estrogen receptor alpha (ER alpha). Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) have opposite effects on carcinogenesis, with DHA suppressing and AA promoting tumor growth both in vitro and in vivo. However, the mechanism is not clear. Here, we examined whether the effect is mediated through changes in ER alpha distribution. MCF-7 cells, an ER alpha-positive human breast cancer cell line, was cultured in estrogen-free medium containing 0, 10 or 60 mu M DHA or AA, then were stimulated with estradiol. DHA supplementation resulted in down-regulation of ER alpha expression (particularly in the extranuclear fraction), a reduction in phosphorylated MAPK, a decrease in cyclin D1 levels and an inhibition in cell viability. In contrast, AA had no such effects. The DHA-induced decrease in ER alpha expression resulted from proteasome-dependent degradation and not from decreased ER alpha mRNA expression. We propose that breast cancer cell proliferation is inhibited by DHA through proteasome-dependent degradation of ER alpha, reduced cyclin D1 expression and inhibition of MAPK signaling. (C) 2010 Elsevier Inc. All rights reserved.