Evaluation of Estrogenic/Antiestrogenic Activity of Ellagic Acid via the Estrogen Receptor Subtypes ERα and ERβ

Ellagic acid is a plant-derived polyphenol, possessing antioxidant, antiproliferative, and antiatherogenic properties. Whether this compound has estrogenic/antiestrogenic activity, however, remains largely unknown. To answer this question, we first investigated the ability of ellagic acid to influence the activity of the estrogen receptor subtypes ERα and ERβ in HeLa cells. Cells co-transfected with an estrogen response element (ERE)-driven luciferase (Luc) reporter gene and an ERα- or ERβ-expression vector were exposed to graded concentrations of ellagic acid. At low concentrations (10-7 to 10-9 M), this compound displayed a small but significant estrogenic activity via ERα, whereas it was a complete estrogen antagonist via ERβ. Further evaluation revealed that ellagic acid was a potent antiestrogen in MCF-7 breast cancer-derived cells, increasing, like the pure estrogen antagonist ICI182780, IGFBP-3 levels. Moreover, ellagic acid induced nodule mineralization in an osteoblastic cell line (KS483), an effect that was abolished by the estrogen antagonist. Endometrium-derived epithelial cells (Ishikawa) showed no response to the natural compound by using a cell viability assay (MTT). These findings suggest that ellagic acid may be a natural selective estrogen receptor modulator (SERM). Keywords: Ellagic acid; estrogen receptor alpha; estrogen receptor beta; selective estrogen receptor modulator; osteoblasts