Phytoestrogens Induce Differential Estrogen Receptor Alpha- or Beta-Mediated Responses in Transfected Breast Cancer Cells

Abstract

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

Antiosteoporotic compounds from seeds of Cuscuta chinensis

“…It has been shown that ERK induces the AP-1 activation (Karin, 1995), thus kaempferol may promote the ALP activity in UMR-106 cells through similar mechanism. In the presence of ER, kaempferol activated AP-1 more potently than quercetin, which well resembles other finding that kaempferol antagonizes estradiol more potently than quercetin (Zava et al, 1997;Harris et al, 2005). Interestingly, isorhamnetin exhibited inhibitory effect on AP-1 activation in the presence of ER subtypes, suggesting its action may be different with quercetin or kaempferol.…”

“…Quercetin and kaempferol activated AP-1 reporter by both ER␣ and ER␤, which makes them behave more like ER antagonists. This further demonstrated previous observation that kaempferol and quercetin antagonized 17␤-estradiol, and kaempferol was more potent than quercetin (Zava et al, 1997;Harris et al, 2005). Contrary to quercetin and kaempferol, isorhamnetin (10-50 M) inhibited AP-1 reporter expression in the presence of ER␣ or ER␤.…”

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

“…We extensively investigated the effects of various steroidal compounds on the transcriptional regulation by Tip60. Consistent with the previous findings (36,60,61), we found that estrogenic compounds (E 2 and DPN) and phytoestrogens (GEN, EQ, DAI, and API) up-regulated ER␤1 transactivation at ERE, whereas SERMs (TAM and RAL) and antiestrogen (ICI) did the opposite. Surprisingly, DPN, GEN, and EQ abolished Tip60-mediated inhibition at the ERE site.…”

Estrogen receptor signaling protects against immune suppression by UV radiation exposure

“…Estrogenic activity of equol has been identified by others in cultured human cells (12,13) and in healthy humans (14). Equol has been shown to bind to both estrogen receptor (ER) ␣ and ER-␤ and to effectively activate both receptors, although with greater transactivation of ER-␤ (13,15). Furthermore, antioxidant response elements associated with the ERs have been described (16), so that the antioxidant and estrogenic properties of equol might be functionally linked.…”