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Selective Activation of Estrogen Receptor-ß Transcriptional Pathways by an Herbal Extract

Departments of Obstetrics, Gynecology, and Reproductive Sciences and Center for Reproductive Sciences (A.C., S.P., C.T.-F., D.T., R.T.M., D.C.L.), and Departments of Cellular and Molecular Pharmacology (A.C., S.P., J.O.J., C.T.-F., N.J.C., D.T., R.T.M., T.S.S., M.I.D., D.C.L.), Neurology (J.O.J., M.I.D.), Pharmaceutical Chemistry (N.J.C., T.S.S.), and Medicine (F.S.), University of California, San Francisco, San Francisco, California 94143; and Bionovo Inc. (I.C., M.T.), Emeryville, California 94608

Address all correspondence and requests for reprints to: Dale C. Leitman, University of California, San Francisco, MS 1258, P.O. Box 0556, San Francisco, California 94143-0556. E-mail: leitmand{at}obgyn.ucsf.edu.

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)-ß subtype inhibits breast cancer cell proliferation. To establish whether ERß-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 ERß selective. MF101 promoted ERß, but not ER, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERß. The ERß selectivity was not due to differential binding because MF101 binds equally to ER and ERß. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ER from ERß when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERß 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 ERß-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes.

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