Estrogen receptor β acts as a dominant regulator of estrogen signaling

Abstract

The physiological e ects of estrogens are mediated by two intracellular transcription factors, the estrogen receptors (ERs), that regulate transcription of target genes through binding to speci®c DNA target sequences. Here we describe alterations in cellular responses to di erent ER agonists and to the anti-estrogenic compound tamoxifen resulting from co-expression of the two ERs in transient co-transfection experiments. Our results demonstrate that ERb can act as a negative or positive dominant regulator of ER activity. This is manifested through reduced transcriptional activity at low concentrations of estradiol (E 2 ); increased antagonistic e ects of tamoxifen on E 2 stimulated activity; and enhanced agonistic action of the phytoestrogenic compound genistein. Furthermore, using chimeric proteins lacking the N-terminal activation function 1 (AF-1), we show that the di erential responses of ERa and ERb to di erent agonists and antagonists are primarily dictated by inherent di erences in the C-terminal ligand-binding domains of the receptors, whereas the magnitude of transcriptional activity is in¯uenced by ERa AF-1, but not ERb AF-1. The ERa AF-1 activity appears to be modulated upon co-expression of both ERs. The alterations in transcriptional activity resulting from co-expression of ERa and ERb are probably due to the formation of a/b heterodimeric complexes. This study demonstrates that co-localization and subsequent heterodimerization of ERa and ERb may result in receptor activity distinct from that of ER homodimers.

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

“…Several reports have described loss of ERb during mammary tumorigenesis, supporting the potential role of ERb as a tumor suppressor (Park et al, 2003;Shaaban et al, 2003;Bardin et al, 2004;Rody et al, 2005). ERb has been reported to modulate ERa activity and cellular response to estrogen (Hall and McDonnel, 1999;Pettersson et al, 2000). Moreover, loss of ERb was observed to be associated with tamoxifen resistance whereas increase of ERb expression in MCF-7 cells enhanced the antiproliferative and apoptotic effect of antiestrogens (HodgesGallagher et al, 2008).…”

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

“…The presence of both ERa and ERb and/or several isoforms of each may account for the observed biphasic response to estrogen agonists. Recent reports suggested the importance of ERb as a negative regulator of ERa function in the nucleus (Petersen et al, 1998;Pettersson et al, 2000) and in cytosol (Acconcia et al, 2005b). Truncated isoforms of ERa can also dimerize with the full size isoform (Stauffer et al, 2000).…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…These findings show the importance of ERα in mediating E2 actions in the development of the mammary gland. ERβ antagonizes the proliferative activity of ERα in mammary epithelium, which suggests that ERβ plays a tumor-suppressive role with respect to breast tumor development [38,39].…”