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and ERß: Estrogen Receptor Binding Is Only Part of the Isoflavone Story1
Departments of Pharmacology & Toxicology,
*
Pathology and
Microbiology, University of Alabama at Birmingham, Birmingham, AL
2To whom correspondence should be addressed.
 |
INTRODUCTION |
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 TOP INTRODUCTION REFERENCES |
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,
Gao et al. 1999
) but are only weakly uterotrophic
(Fanti et al. 1998
). The discovery of a second estrogen
receptor (ERß) (Kuiper et al. 1996
), a receptor for
which genistein and the natural estrogen 17ß-estradiol have
approximately equal affinity, has provided a new perspective on the
pleiotropic nature of the effects of genistein because ERß is
expressed in differing amounts and in different cells (Kuiper et al. 1997
) from the classical estrogen receptor, ER
. However,
several other biological properties of the isoflavones also contribute
to the complexity of understanding their actions.
After early reports that genistein had inhibitory effects on the
epidermal growth factor receptor (EGF-R) tyrosine kinase activity
(Akiyama et al. 1987
), many investigators attributed
various biological effects of genistein to inhibition of various other
tyrosine kinases. However, in most reports, direct demonstration of
such inhibition was not shown. Indeed, although EGF stimulation of
EGF-R tyrosine autophosphorylation in prostate (Peterson and Barnes 1993
) and breast (Peterson and Barnes 1996
) cancer cells was blocked by tyrphostins (synthetic
tyrosine kinase inhibitors), genistein had no effect. In rats treated
with genistein, the reduced reactivity of EGF-R with
antiphosphotyrosine antibodies was shown instead to result from a
reduction in the amount of EGF-R protein (Dalu et al. 1998
). These data suggest that genistein has its effects
through transcriptional processes rather than directly on tyrosine
kinase activity. If so, then the variable effects of genistein and
other isoflavones in estrogen-sensitive tissues may depend on the
production of paracrine and autocrine growth factors that cause
proliferation of cells that do not express ER or ERß. Not all such
factors may stimulate cell division, however. Transforming growth
factor ß (TGFß), an inhibitor of epithelial cell growth, has both
increased expression (Sathyamoorthy et al. 1998
) and
production (Kim et al. 1998
) in the presence of
genistein in a dose-dependent manner in both normal and transformed
breast epithelial cells. This process may also occur in the vascular
system. In other non-ER–dependent mechanisms, genistein inhibits both
metastasis (Li et al. 1999a
and 1999b
, Schleicher et al. 1999
) and angiogenesis (Fotsis et al. 1993
, Zhou et al. 1999
), two important processes
that lead to death from cancer.
Metabolism of isoflavones may also be a factor. Human breast cancer
cells convert isoflavones to phase I and phase II metabolites
(Peterson et al. 1996
and 1998
). In addition, under cell
culture conditions simulating oxidative bursts, isoflavones are
converted to halogenated and nitrated derivatives (Boersma et al. 1999
). Such metabolism is providing new paradigms for the
study of the anti-inflammatory activity of these and other
polyphenols. These modifications to the isoflavone molecule may
influence their binding to ER or ERß or to other protein targets.
Examination of the crystal structure of the ERß-genistein complex
(Pike et al. 1999
) suggests the following: 1)
the expected orientation of isoflavones in the ligand binding site is
reversed, with the B-ring hydroxyl interacting with the amino acid
residues that are in contact with the 3-hydroxyl group of the aromatic
A ring of 17ß-estradiol; and 2) individual chlorinated
isomers may increase binding to ERß or lead to greater displacement
of the AF-2 helix, which is critical for ligand-dependent
transactivation of ERß.
Although the relative importance of each of these pathways remains to be established, further issues remain unresolved, such as the concentration and composition of isoflavones in the target tissues as opposed to in blood or urine.
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FOOTNOTES |
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REFERENCES |
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TOPINTRODUCTIONREFERENCES |
|---|
1.
Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S.-I., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987;262:5592-5595
2. Blair H., Jordan S. E., Peterson T. G., Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J. Cell. Biochem. 1996;61:629-637[Medline]
3. Boersma B. J., Patel R. P., Kirk M., Darley-Usmar V. M., Barnes S. Chlorination and nitration of soy isoflavones. Arch. Biochem. Biophys. 1999;368:265-275[Medline]
4. Dalu A., Haskel I. J. F., Coward L., Lamartiniere C. A. Genistein, a component of soy, inhibits the expression of the EGF and erbB2/Neu receptors in the rat dorsolateral prostate. Prostate 1998;37:36-43[Medline]
5. Fanti P., Monier-Faugere M. C., Geng Z., Schmidt J., Morris P. E., Cohen D., Malluche H. H. The phytoestrogen genistein reduces bone loss in short-term ovariectomized rats. Osteoporosis Int 1998;8:274-281[Medline]
6.
Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 1993;90:2690-2694
7. Gao Y. H., Yamaguchi M. Inhibitory effect of genistein on osteoclast-like cell formation in mouse marrow cultures. Biochem. Pharmacol. 1999;58:767-772[Medline]
8. Kim H., Peterson T. G., Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role of its effects through transforming growth factor beta signaling pathways. Am J Clin Nutr 1998;68:1418S-1425S[Abstract]
9.
Kuiper G. G., Carlsson B., Grandien K., Enmark E., Haggblad J., Nilsson S., Gustafsson J. A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863-870
10.
Kuiper G. G., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. U.S.A. 1996;93:5925-5930
11.
Li D., Yee J. A., McGuire M. H., Murphy P. A., Yan L. Soybean isoflavones reduce experimental metastasis in mice. J. Nutr. 1999a;129:1075-1078
12. Li Y., Bhuiyan M., Sarkar F. H. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. Int. J. Oncol. 1999b;15:525-533[Medline]
13. Peterson T. G., Barnes S. Isoflavones inhibit the growth of human prostate cancer cell lines without inhibiting epidermal growth factor receptor autophosphorylation. Prostate 1993;22:335-345[Medline]
14. Peterson T. G., Barnes S. Genistein inhibits both estrogen and growth factor stimulated proliferation of human breast cancer cells. Cell Growth Diff 1996;7:1345-1351[Abstract]
15.
Peterson T.G., Coward L., Kirk M., Falany C. N., Barnes S. Isoflavones and breast epithelial cell growth: the importance of genistein and biochanin A metabolism in the breast. Carcinogenesis 1996;17:1861-1869
16. Peterson T. G., Ji G.-P., Kirk M., Coward L., Falany C. N., Barnes S. Metabolism of the isoflavones genistein and biochanin A in human breast cancer cell lines. Am. J. Clin. Nutr. 1998;68:1505S-1511S[Abstract]
17. Pike A. C. W., Brzozowski A. M., Hubbard R. E., Bonn T., Thorsell A.-G., Engstrom O., Ljunggren J., Gustafsson J.-A., Carlquist M. Structure of the ligand binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 1999;18:4608-4618[Medline]
18. Sathyamoorthy N., Gilsdorf J. S., Wang T. T. Differential effect of genistein on transforming growth factor beta 1 expression in normal and malignant mammary epithelial cells. Anticancer Res 1998;18:2449-2453[Medline]
19. Schleicher R. L., Lamartiniere C. A., Zheng M., Zhang M. The inhibitory effect of genistein on the growth and metastasis of a transplantable rat accessory sex gland carcinoma. Cancer Lett 1999;136:195-201[Medline]
20.
Zhou J. R., Gugger E. T., Tanaka T., Guo Y., Blackburn G. L., Clinton S. K. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J. Nutr. 1999;129:1628-1635
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