Selective activation of estrogen receptor-beta transcriptional pathways by an herbal extract.
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.
Cvoro
Aleksandra
A
University of California, San Francisco, MS 1258, P.O. Box 0556, San Francisco, California 94143-0556, USA. leitmand@obgyn.ucsf.edu
Paruthiyil
Sreenivasan
S
Jones
Jeremy O
JO
Tzagarakis-Foster
Christina
C
Clegg
Nicola J
NJ
Tatomer
Deirdre
D
Medina
Roanna T
RT
Tagliaferri
Mary
M
Schaufele
Fred
F
Scanlan
Thomas S
TS
Diamond
Marc I
MI
Cohen
Isaac
I
Leitman
Dale C
DC
D031403:Anemarrhena / Q000737:chemistry*; D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004054:Diethylstilbestrol; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D010936:Plant Extracts / Q000378:metabolism / Q000494:pharmacology*; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014183:Transplantation, Heterologous; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D002273:Carcinogens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C517398:MF101 extract; D010936:Plant Extracts; D004054:Diethylstilbestrol