Figure 2

Molecular effects of oestradiol and anti-oestrogen compounds. Shown are the molecular effects of (a) oestradiol, (b) the selective oestrogen receptor modulator (SERM) tamoxifen and (c) the selective oestrogen receptor downregulator (SERD) fulvestrant on oestrogen receptor (ER) dimerization, conformational shape and DNA binding by liganded receptor, AF1/AF2 activation, coactivator recruitment, and subsequent transcriptional activation of type I and type II ER-regulated genes. As shown in panel a, oestradiol binding to ER leads to loss of heat shock proteins (HSPs), dimerization and phosphorylation of receptors, with conformational change leading to coactivator activation at both AF1 and AF2 sites; a full agonist effect is seen. In panel b, SERM (tamoxifen) binding to ER leads to loss of HSPs, dimerization and phosphorylation of receptors, but with different specific conformational change leading to coactivator activation at AF1 only, and not at AF2 sites; therefore, a partial agonist effect is seen. As shown in panel c, SERD (fulvestrant) binding to ER leads to loss of HSPs, but lack of receptor dimerization because of altered conformational change. Thus, receptor degradation is enhanced with no activation at AF1 or AF2 sites; no agonist effect is seen. AF, activating function; E, oestradiol; ERE, oestrogen response element; F, fulvestrant; RNA Pol II, ribonucleic acid polymerase II; T, tamoxifen.