Exploitation of the relationship between estrogen receptor (ER) structure and 
activity has led to the development of 1) selective ER modulators (SERM), 
compounds whose relative agonist/antagonist activities differ between target 
tissues; 2) selective ER degraders (SERD), compounds that induce a 
conformational change in the receptor that targets it for proteasomal 
degradation; and 3) tissue-selective estrogen complexes (TSEC), drugs in which a 
SERM and an ER agonist are combined to yield a blended activity that results in 
distinct clinical profiles. In this study, we have performed a comprehensive 
head-to-head analysis of the transcriptional activity of these different classes 
of ERM in a cellular model of breast cancer. Not surprisingly, these studies 
highlighted important functional differences and similarities among the existing 
SERM, selective ER degraders, and TSEC. Of particular importance was the 
identification of genes that were regulated by various TSEC combinations but not 
by an estrogen or SERM alone. Cumulatively, the findings of this analysis are 
informative with respect to the mechanisms by which ER is engaged by different 
enhancers/promoters and highlights how promoter context influences the 
pharmacological activity of ER ligands.