Resveratrol Acts as a Mixed Agonist/Antagonist for Estrogen Receptors α and β

Abstract Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors α and β (ERα and ERβ). Resveratrol, trans-3,5,4′-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERα vs. ERβ in this binding is unknown. Here we report that resveratrol binds ERβ and ERα with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERβ with higher affinity than ERα. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERα or ERβ. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERβ has higher transcriptional activity than E2-liganded ERβ at a single palindromic ERE. This indicates that those tissues that uniquely express ERβ or that express higher levels of ERβ than ERα may be more sensitive to resveratrol’s estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERα with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERβ. These data indicate that resveratrol differentially affects the transcriptional activity of ERα and ERβ in an ERE sequence-dependent manner.