Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer

Abstract

Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.

Fig. (1)

Schematic comparison of human ER-α and ER-β structure. The structural domains are shown, and the percentage of amino acid identity shared by the two ERs is indicated for each domain. The horizontal bars highlight areas of different functions.

Fig. (2)

Schematic representation of different liganded-ER complexes interacting with co-regulators and consequent transcriptional activities. ERs that bind to estrogenic ligands interact with co-activators (CoA) and activate transcription. Anti-estrogen liganded-ER complexes interact with co-repressors (CoR) and inactivate transcription of responsive genes. Selective estrogen receptor modulators (SERMs) bind to ERs and interact with either co-activator or co-repressor complexes eliciting partial transcriptional activity depending upon the cellular context.

Fig. (3)

SERMs with a structure mimicking tamoxifen containing a triphenylethylene core.

Fig. (4)

SERMs with a structure mimicking raloxifene.

Fig. (5)

Steroidal SERMs

Fig. (6)

Structure of ERβ-selective agonists.