TY - JOUR
T1 - Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens
AU - Jiang, Yan
AU - Gong, Ping
AU - Madak-Erdogan, Zeynep
AU - Martin, Teresa
AU - Jeyakumar, Muthu
AU - Carlson, Kathryn
AU - Khan, Ikhlas
AU - Smillie, Troy J.
AU - Chittiboyina, Amar G.
AU - Rotte, Sateesh C.K.
AU - Helferich, William G.
AU - Katzenellenbogen, John A.
AU - Katzenellenbogen, Benita S.
PY - 2013/11
Y1 - 2013/11
N2 - Because little is known about the actions of botanical estrogens (BEs), widely consumed by menopausal women, we investigated the mechanistic and cellular activities of some major BEs. We examined the interactions of genistein, daidzein, equol, and liquiritigenin with estrogen receptors ERa and ERβ, with key coregulators (SRC3 and RIP140) and chromatin binding sites, and the regulation of gene expression and proliferation in MCF-7 breast cancer cells containing ERa and/or ERβ. Unlike the endogenous estrogen, estradiol (E2), BEs preferentially bind to ERβ, but their ERβ-potency selectivity in gene stimulation (340- to 830-fold vs. E2) is enhanced at several levels (coregulator recruitment, chromatin binding); nevertheless, at high (0.1 or 1 μM) concentrations, BEs also fully activate ERa. Because ERa drives breast cancer cell proliferation and ERβ dampens this, the relative levels of these two ERs in target cells and the BE dose greatly affect gene expression and proliferative response and will be crucial determinants of the potential benefits vs. risks of BEs. Our findings reveal key and novel mechanistic differences in the estrogenic activities of BEs vs. E2, with BEs displaying patterns of activity distinctly different from those seen with E2 and provide valuable information to inform future studies.
AB - Because little is known about the actions of botanical estrogens (BEs), widely consumed by menopausal women, we investigated the mechanistic and cellular activities of some major BEs. We examined the interactions of genistein, daidzein, equol, and liquiritigenin with estrogen receptors ERa and ERβ, with key coregulators (SRC3 and RIP140) and chromatin binding sites, and the regulation of gene expression and proliferation in MCF-7 breast cancer cells containing ERa and/or ERβ. Unlike the endogenous estrogen, estradiol (E2), BEs preferentially bind to ERβ, but their ERβ-potency selectivity in gene stimulation (340- to 830-fold vs. E2) is enhanced at several levels (coregulator recruitment, chromatin binding); nevertheless, at high (0.1 or 1 μM) concentrations, BEs also fully activate ERa. Because ERa drives breast cancer cell proliferation and ERβ dampens this, the relative levels of these two ERs in target cells and the BE dose greatly affect gene expression and proliferative response and will be crucial determinants of the potential benefits vs. risks of BEs. Our findings reveal key and novel mechanistic differences in the estrogenic activities of BEs vs. E2, with BEs displaying patterns of activity distinctly different from those seen with E2 and provide valuable information to inform future studies.
KW - Breast cancer cells
KW - Chromatin binding
KW - Gene regulation
KW - Proliferation
UR - http://www.scopus.com/inward/record.url?scp=84887088487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887088487&partnerID=8YFLogxK
U2 - 10.1096/fj.13-234617
DO - 10.1096/fj.13-234617
M3 - Article
C2 - 23882126
AN - SCOPUS:84887088487
SN - 0892-6638
VL - 27
SP - 4406
EP - 4418
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -