AF–1 could be activated even in a ligand–independent manner, depending on the phosphorylation status of ERs (Marino et al. 2006). In particular, the Ser118 residue in AF–1 region of ERα, and Ser106 and Ser124 residues in the AF–1 region of ERβ, are phosphorylation sites essential for the ligand–independent activation of ER through the intracellular signaling cascades (Deblois and Giguere 2003; Thomas et al. 2008).