Novel estrogenic therapies are needed that ameliorate menopausal symptoms and have the bone-sparing effects of endogenous estrogens but do not promote breast or uterine cancer. Recent evidence suggests that selective activation of the estrogen receptor (ER)-β subtype inhibits breast cancer cell proliferation. To establish whether ERβ-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERβ selective. MF101 promoted ERβ, but not ERα, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERβ. The ERβ selectivity was not due to differential binding because MF101 binds equally to ERα and ERβ. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ERα from ERβ when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERβ to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ERα-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model.Ourresults demonstrate that herbal ERβ-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes.
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