Estrogen Receptors as Therapeutic Targets in Breast Cancer

Abstract

While estrogen receptor (ER)-targeted therapeutics have clearly been a success in the treatment of breast cancer, the orphan estrogen-related receptors (ERRs) represent novel targets for future development. The ERRs, comprising ERRalpha, ERRbeta and ERRgamma, bind and regulate transcription via estrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs), but do not bind endogenous estrogens. The emerging role of ERRalpha and ERRgamma in modulating estrogen responsiveness, substituting for ER activities, and serving as prognosticators in breast and other cancers is providing an impetus for the identification of compounds which target these proteins. Moreover, ERRalpha plays a role in energy homeostasis and will likely be targeted for the treatment of metabolic disorders. Multiple classes of synthetic ligands have already been identified. The phytoestrogens genistein, daidzein, biochanin A and 6,3'4'-tryhydroxyflavone have been reported as ERRalpha agonists. The phenolic acyl hydrazones GSK4716 and GSK9089 act as selective agonists of ERRbeta and ERRgamma. The organochlorine pesticides toxaphene and chlordane, and the synthetic compound XCT790 antagonize ERRalpha. The synthetic estrogen diethylstilbestrol antagonizes all three ERRs. The selective estrogen receptor modulators 4-hydroxytamoxifen and 4-hydroxytoremifene antagonize ERRgamma. The rational development of synthetic ligands for the ERRs may soon provide new agents to supplement the repertoire of antihormonal therapies to combat breast cancer. Moreover, expression of ERRs in other cancers and metabolic disorders may provide a targeted treatment strategy for these patients as well.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

“…1 The discovery of the ER antagonist tamoxifen represented a breakthrough in targeted cancer therapy with activity due to the formation of the 4-hydroxy metabolite, which mimics the phenol of the endogenous ligand estradiol (1). 2 Considerable efforts have been made to develop alternative selective estrogen receptor modulators (SERMs) with a common issue encountered being that the phenol moiety required for high levels of binding to the estrogen receptor frequently leads to low bioavailability, often attributed to glucuronidation of the phenol.…”

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

“…This was particularly true once the nonsteroidal antiestrogens were recognized to be SERMs [101][102][103] and had applications not only for the treatment and prevention of breast cancer but also as potential agents to treat osteoporosis and coronary heart disease [104,105]. The reader is referred to other recent review articles to obtain further details of new medicines under investigation [104,105] but some current examples are worthy of note and will be mentioned briefly. Compounds of interest that have their structural origins as metabolites from nonsteroidal antiestrogens are summarized in Figure 7.…”

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

“…Hormone ablation therapy, using ER antagonists, are currently a common first-line therapy for ER-positive breast cancers and function by eliciting cell-cycle arrest in hormone-dependant breast cancer cells (Sutherland et al, 1983;Jensen and Jordan, 2003). Although these anti-estrogen therapies are initially effective, B50% of ER-positive patients develop resistance within their lifetime, ultimately leading to therapeutic failure (Encarnacion et al, 1993;Robertson, 1996;Barker, 2003;Ariazi et al, 2006). As such, a significant fraction of patients with ER-positive disease require adjuvant therapies.…”