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