Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Abstract

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging.

Figure 1

Schematic diagram of the two human estrogen receptors, ERα and ERβ. Both receptors consist of six functional domains, including the DNA-binding domain (DBD), the ligand-binding domain (LBD), the ligand-independent activation function AF-1, and the ligand-dependent activation function AF-2. The percentage identity between the two receptors is indicated.

Figure 2

ER regulation by a variety of signals. Growth factors such as epidermal growth factor, insulin-like growth factor-1, insulin, and transforming growth factor-β bind to and activate their receptors, which in turn activate the RAS–RAF–ERK and the phosphoinositide 3-kinase (PI3K) pathways; the activated kinases then phosphorylate and activate ER. Other extracellular stimuli such as dopamine and cyclic AMP bind G-protein-coupled receptors and activate adenylyl cyclase (AC) and protein kinase A (PKA), which subsequently phosphorylate and activate ER. ER can also interact directly with components of the cytosolic signaling molecules, including the regulatory subunit of PI3K, leading to the activation of the serine/threonine kinase Akt. In the nucleus, hormone binding results in receptor dimerization and recruitment of coactivators or corepressors depending on the bound ligand, leading to transcriptional activation or repression. ERE, estrogen response element; MEK, MAP kinase/ERK kinase; SERM, selective estrogen receptor modulator.

Figure 3

Therapy for women with ER-positive breast tumors.

Figure 4

Chemical structures of the three FDA-approved selective estrogen receptor modulators (SERMs), the pure antiestrogen Faslodex, and the aromatase inhibitors (AIs). The SERMs include the triphenylethylenes tamoxifen and toremifene, and the benzothiophene raloxifene. AIs include the nonsteroidal anastrazole and letrozole, and the steroidal exemestane.