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)-␤ subtype inhibits breast cancer cell proliferation. To establish whether ER␤-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101,

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... d to treat hot flashes, are ER␤ selective. MF101 promoted ER␤, but not ER␣, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ER␤. The ER␤ selectivity was not due to differential binding because MF101 binds equally to ER␣ and ER␤. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ER␣ from ER␤ when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ER␤ to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ER␣-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model. Our results demonstrate that herbal ER␤-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes. (Endocrinology 148: 538 -547, 2007)