Antiestrogens: structure activity relationships and use in breast cancer treatment: Beyond the Abstract

Estrogen receptor alpha (ERα) plays a role in about 70% of breast cancers, mediating the proliferative effects of estrogens. Antiestrogens (AEs) are synthetic molecules developed in order to compete with estrogens and inhibit the transcriptional activity of ERα. AEs have been traditionally classified into two main categories.

Selective ER Modulators (SERMs) such as tamoxifen or raloxifene are mainly antagonists in breast and have a partial agonist activity in other tissues, such as the uterus (limiting the use of tamoxifen in the clinic) or bone (exploited for prevention of osteoporosis by raloxifene). On the other hand, Selective ER Downregulators (SERDs), or pure AEs, are antagonists in all tissues and increase the turnover of ERα via the ubiquitin – proteasome pathway. SERDs can block proliferation of tumors resistant to SERMs, suggesting different mechanisms of action. However, some compounds present a partial agonist profile as well as the ability to induce ER degradation to lower extents (e.g. bazedoxifene, GW7604), suggesting that the classification of AEs should be considered more as a spectrum, with increasing turnover efficiency correlating with decreasing agonism potential (Fig. 1).  

Crystallography studies have indicated that AEs induce a variety of different conformational changes of the transcriptional activation region in the ERα ligand binding domain, consistent with differential recruitment of cofactors forming the basis for the cell- and gene-specific activity profiles of AEs. Interestingly, AEs induce ERα SUMOylation in a manner that parallels ubiquitination and SERD activity. In addition to increasing ER turn-over, ERα post-translational modifications (PTMs) could alter its interactome, leading to a stronger recruitment of corepressors blocking ERα transcriptional activity. 

Mutations in the ligand binding domain of ERα have been recently characterized in breast cancer patients resistant to endocrine therapies. These mutants often have a high constitutive activity, due to the adoption of an agonist-like unliganded conformation, but also appear to result in reduced efficacy of AEs in cell models. In-depth studies of the PTMs, cofactor recruitment and turnover rates induced by AEs on the different ERα mutants are important to better characterize the mechanisms of action of AEs and inform treatment choice on a personalized basis.

Fig. 1: Spectrum of partial agonist activity and ERα turnover rate in steroidal and non-steroidal antiestrogens.

Written by: Tatiana Traboulsi, Mohamed El Ezzy and Sylvie Mader

Institute for Research in Immunology and Cancer
Department of Biochemistry
Université de Montréal
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