Research Resource: Transcriptional Profiling in a Cellular Model of Breast Cancer Reveals Functional and Mechanistic Differences Between Clinically Relevant SERM and Between SERM/Estrogen Complexes

Abstract

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.

mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells

“…Since expression values are log2 transformed intensity values, a difference in expression by one unit corresponds to a twofold mean change in probe intensities. For comparison, corresponding differences between tamoxifen treated MCF7 cells and the average of vehicle control cells in the GEO:GSE35428 dataset [42] were also included in the heatmap. A Bioconductor ExpressionSet for GSE35428 was retrieved using the GEOquery package (2.32.0) [43].…”

Cooperative Activation of Gene Expression by Agonists and Antagonists Mediated by Estrogen Receptor Heteroligand Dimer Complexes

“…However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist (Chang et al, 2010;Wardell et al, 2012). We demonstrate that ER agonist/antagonist combined treatment can cooperatively activate gene expression through an ER-HLD complex consisting of one receptor monomer bound to agonist and another occupied by antagonist.…”

“…Two recent microarray experiments demonstrated that, in MCF-7 cells treated with estrogen and SERMs, alone or in combination, there is a subset of genes induced to a greater extent by combined estrogen and SERM treatment than by either single agent (Chang et al, 2010;Wardell et al, 2012). The ability of ER-HLD to cooperatively regulate gene expression induced by combined agonist/antagonist treatments provides a possible mechanistic explanation for the induction, rather than the inhibition, of the expression of these genes.…”

“…Thus, antiestrogens (e.g., tamoxifen) block E2 binding to ERa and antagonize estrogen-stimulated gene expression, which is highly desirable relative to breast cancer prevention and treatment. However, recent MCF-7 breast cancer cell microarray experiments revealed a group of novel genes cooperatively regulated by ERa agonist and antagonist (Chang et al, 2010;Wardell et al, 2012). This is difficult to reconcile with competitive antagonism, and argues for an additional model for combined agonist/antagonist regulation of ER activity.…”

27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy

“…ER ligands differ in their structures and their effects on ER conformation (26)(27)(28)(29). For example, Wardell et al tested 6 different ER ligands and observed different gene expression patterns regulated by different ER-ligand complexes (29). Unliganded ERα can also bind to chromatin and regulate gene expression (30).…”