Estrogen signaling pathway

The estrogen signaling pathway entails the binding of endogenous estrogens (such as 17β-estradiol) to estrogen receptors, chiefly Estrogen receptor alpha (ERα) and Estrogen receptor beta (ERβ), which are members of the nuclear hormone receptor superfamily. Upon ligand binding, these receptors act as ligand-activated transcription factors by dimerizing, translocating to the cell nucleus, and binding to estrogen response elements (EREs) on DNA to regulate gene expression. In addition to genomic signaling, estrogen receptors also participate in rapid, non-genomic signaling through membrane-associated receptors, including the G protein-coupled estrogen receptor (GPER1). The pathway regulates diverse biological processes such as cell proliferation, apoptosis, and tissue differentiation and is of major importance in reproductive biology and in hormone-responsive cancers. Drugs targeting this pathway include SERMs, SERDs, and aromatase inhibitors. Clinical challenges include drug resistance, tissue-specificity of agonism/antagonism, and adverse effects associated with systemic estrogen modulation.

Other names

ERαERβNuclear estrogen receptorOestrogen receptorEstrogen receptor alphaEstrogen receptor betaG protein-coupled estrogen receptor 1

Estrogen receptor antagonism (e.g., tamoxifen blocks ligand binding); Estrogen receptor degradation (e.g., fulvestrant promotes degradation of ER); Selective receptor modulation (SERMs have different effects in different tissues); Ligand binding inhibition; Downregulation of target gene expression by blocking receptor-DNA interaction