Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects?

Abstract

In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.

Keywords: cancer; cell signaling; epigenetic regulation; estrogen receptor; ligand; selective estrogen receptor modulators; transcription; xenoestrogens.

Figure 1

Structure and mechanisms of action of the estrogen receptor (ER). (A) The evolutionarily conserved domains of several nuclear receptors, including ER, AR (androgen receptor), PR (progesterone receptor), GR (glucocorticoid receptor), VDR (vitamin D receptor), RAR (retinoid acid receptor) and TR (thyroid receptor). Domains involved in DNA and ligand binding, as well as in dimerization, ligand-independent transactivation function (AF1) and ligand-dependent transactivation function (AF2) are shown. The number of amino acids for each domain is presented. The approximate molecular weight of each nuclear receptor is also indicated on the right side; (B) estradiol (E2) mediates multiple phenotypic changes in cells by binding to its receptor. E2 enter the cell through the lipid membranes and binds ER in the cytoplasm or the nucleus. ER mediates E2 effects through diverse transcriptional mechanisms. In the nucleus, the activated ER forms a dimer to tightly fix DNA directly at the ERE sites or indirectly at Sp1 or Ap1 sites. The activated ER is then able to recruit cofactors and RNA polymerase II (pol. II), which allows the transcription of target genes (ER genomic action). Furthermore, ERs can use rapid non-genomic action through the activation of intracellular kinases related or not to the growth factor signaling.

Figure 1

Structure and mechanisms of action of the estrogen receptor (ER). (A) The evolutionarily conserved domains of several nuclear receptors, including ER, AR (androgen receptor), PR (progesterone receptor), GR (glucocorticoid receptor), VDR (vitamin D receptor), RAR (retinoid acid receptor) and TR (thyroid receptor). Domains involved in DNA and ligand binding, as well as in dimerization, ligand-independent transactivation function (AF1) and ligand-dependent transactivation function (AF2) are shown. The number of amino acids for each domain is presented. The approximate molecular weight of each nuclear receptor is also indicated on the right side; (B) estradiol (E2) mediates multiple phenotypic changes in cells by binding to its receptor. E2 enter the cell through the lipid membranes and binds ER in the cytoplasm or the nucleus. ER mediates E2 effects through diverse transcriptional mechanisms. In the nucleus, the activated ER forms a dimer to tightly fix DNA directly at the ERE sites or indirectly at Sp1 or Ap1 sites. The activated ER is then able to recruit cofactors and RNA polymerase II (pol. II), which allows the transcription of target genes (ER genomic action). Furthermore, ERs can use rapid non-genomic action through the activation of intracellular kinases related or not to the growth factor signaling.

Figure 2

Illustration of the chemical structures of different groups of phytoestrogens. Ex: Example.

Figure 3

Different targets of phytoestrogens in cells. Cell signaling pathways for estrogens through the nuclear receptors ERα, ERβ and the transmembrane receptor G-protein-coupled ER (GPER; formerly known as GPR30) [136] are shown. Phytoestrogens are able to inhibit mitogenic pathways via ERα or PI3K/MAPK, which in turn inhibit cancer cell proliferation and invasion by modifying AKT, p70S6K and ERK1/2 phosphorylation as well as interaction between ERα with various coregulatory proteins such as calmodulin (CaM). Activation of ERβ inhibits dedifferentiation pathways and induces apoptosis and cell cycle arrest. GPER activation is anti-tumorigenic, as it upregulates p21 and induces cell cycle arrest in prostate cancer [137]. Epigenetic modifications by phytoestrogens, such as demethylation of CpG islands within the promoters of tumor suppressor genes, could contribute to cell growth arrest. Inhibition of proteasomes by phytoestrogens also appears to be another mechanism of phytoestrogen activity in decreasing cancer cell survival.