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Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens
Author(s) -
Jiang Yan,
Gong Ping,
MadakErdogan Zeynep,
Martin Teresa,
Jeyakumar Muthu,
Carlson Kathryn,
Khan Ikhlas,
Smillie Troy J.,
Chittiboyina Amar G.,
Rotte Sateesh C. K.,
Helferich William G.,
Katzenellenbogen John A.,
Katzenellenbogen Benita S.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-234617
Subject(s) - estrogen receptor , genistein , estrogen , selective estrogen receptor modulator , estrogen receptor alpha , chemistry , tamoxifen , medicine , cancer research , breast cancer , endocrinology , biology , cancer
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 ERα 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 ERα 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 ERα. Because ERα 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.—Jiang, Y., Gong, P., Madak‐Erdogan, Z., Martin, T., Jeyakumar, M., Carlson, K., Khan, I., Smillie, T. J., Chittiboyina, A. G., Rotte, S. C. K., Helferich, W. G., Katzenellenbogen, J. A., Katzenellenbogen, B. S. Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens. FASEB J . 27, 4406–4418 (2013). www.fasebj.org