Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens.

Abstract

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.

• Authors: Yan Jiang, Ping Gong, Zeynep Madak-Erdogan, Teresa Martin, Muthu Jeyakumar, Kathryn Carlson, Ikhlas Khan, Troy J Smillie, Amar G Chittiboyina, Sateesh C K Rotte, William G Helferich, John A Katzenellenbogen, Benita S Katzenellenbogen
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 11 Pg. 4406-18 (Nov 2013) ISSN: 1530-6860 [Electronic] United States
• PMID: 23882126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Chromatin
• Estrogen Receptor alpha
• Estrogen Receptor beta
• NRIP1 protein, human
• Nuclear Proteins
• Nuclear Receptor Interacting Protein 1
• Phytoestrogens
• Estradiol
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Binding Sites
• Cell Proliferation
• Chromatin (metabolism)
• Dose-Response Relationship, Drug
• Estradiol (pharmacology)
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (metabolism)
• Humans
• MCF-7 Cells
• Nuclear Proteins (metabolism)
• Nuclear Receptor Coactivator 3 (metabolism)
• Nuclear Receptor Interacting Protein 1
• Phytoestrogens (pharmacology)
• Transcription, Genetic