Figure 2: Structure and mechanisms of action of estrogen receptors. (a) ERα and ERβ have an evolutionary conserved modular structure. The percentages of homology between the two forms are presented. The localizations of the ligand-binding domain (LBD) within the E domain and the DNA-binding domain (DBD) within the C domain are also presented. ERs possess two transactivation functions (AF-1 and AF-2), each divided into two subdomains which regulate the expression of target genes and contain a nuclear localization signal (NLS). (b) Due to its lipophilic properties, estradiol (E2) can passively enter the cell, through the lipid membranes. E2 can then bind ERs in the cytoplasm or the nucleus. ER dimers bind to the chromatin to modulate target gene expression. This mechanism corresponds to the genomic action of ERs, but ERs can also exercise nongenomic action, fast, directly in the cytoplasm. Indeed, the cytoplasmic or membrane-bound fraction of ER can induce, after E2-binding, the activation of intracellular signaling pathways independently or in association with the growth factor pathways.