o estrogen receptors (ERs) are members of the nuclear receptor superfamily that upon ligand activation undergo conformational changes, oligomerize and act as transcription factors. Like other nuclear receptors, ERs are characterized by the presence of the ligand binding (LBD), DNA binding (DBD), and two activation domains. The N-terminal activation domain AF1 stimulates transcription in a ligand-independent manner whereas the C-terminaI AF2 is ligand-dependent. In the inactive state the ERs are in a complex with chaperones and co-chaperones whose assembly follows a stepwise route. While all steroid hormones receptors shuttle between the cytoplasm and the nucleus, ERs are primarily nuclear. The receptors have overlapping but also distinct expression patterns in many tissues. For instance, Esr1 is primarily expressed in the uterus, liver, heart and kidney while Esr2 is primarily expressed in the ovary, prostate, gastrointestinal tract, bladder and lung. Upon ligand binding the receptors dissociate from the chaperones and form homo- and heterodimers that bind to cognate DNA sites known as Estrogen Response Elements (ERE) to directly affect the transcription of target genes. ERs action can also be indirect via interactions with other transcription factors. Coregulators - coactivators and corepressors, interact with the receptors and modulate their transcriptional activity. Primary coactivators bind directly to the receptors whereas secondary coactivators exert their effect via other protein-protein interactions and/or molecular modifications. As mentioned, the receptors may be found membrane tethered (mERs) to induce rapid effects. The pathway mediated by Gper also promotes rapid responses involving increase in cAMP which could then activate PKA pathway. Both mERs and probably Gper associate with Src tyrosine kinase eventually leading to activation of growth factor signaling, particularly epidermal growth factor (via Hbegf) and the downstream intracellular pathways. While estrogen is a bona fide Gper ligand  there are still controversies regarding Gper's function. Estrogen is involved in the growth and development of breast cancers; estrogen mediated transcription is constitutively active in more than 50% of cases. Estrogen-Src axis may play a role in estrogen-dependent breast cancer. Dysregulated miRNAs appear to correlate with the expression of estrogen receptor while others are under the receptor's transcriptional control. The development of anti-estrogen drugs follows two pharmacological approaches. One targets the receptor; drugs are  either 'pure' antagonists, eg. fulvestran or mixed agonist-antagonists known as selective modulators (SERMs), eg. tamoxifen. The widely used tamoxifen acts as an antagonist in breast cancer cells but is an agonist in bone and the cardiovascular system. The second targets estrogen biosynthesis via the development of aromatase inhibitors (to see the overall anti-estrogen drug pathway, click here). To see the Ontology Report for annotations, GViewer and download, click here
[Click the see the ontology report for related GO term - GO:0030520]

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