Abstract

The differential impact of distinct antiestrogens (AEs) is the result of varying structural perturbations they confer to estrogen receptors (ERs) when these small-molecule synthetic compounds compete with endogenous hormones, such as 17β-estradiol. These structural changes translate to altered ability of ERs to conscript cofactors and consequently alter the transcription of their target genes. AEs, depending on the mechanism of action, are classified as either selective estrogen receptor modulators (SERMs), which display tamoxifen-like partial agonism, or as selective estrogen receptor downregulators (SERDs) that confer structurally induced posttranslational modifications (PTMs) that destine these receptors for proteosomal degradation. The conformational plasticity of the ER helix 12 (H12) and how its dynamics and conformational sampling is altered by different AEs are crucial to cofactor recruitment and selectivity, translating to varying degrees of receptor modulation and downstream functional effects. Dissecting these conformational state fluctuations within the context of variable cofactor profiles in different tissues, PTM induction, and emergence of hormonal treatment-related resistance mutations in ERs could lead to improved design of novel therapeutic molecules for breast cancer.

Keywords
Nuclear receptor Estrogen Tamoxifen Breast cancer SERM Raloxifene