The Estrogen Receptor α-Cistrome Beyond Breast Cancer

Abstract

Although many tissues express estrogen receptor (ER)α, most studies focus on breast cancer where ERα occupies just a small fraction of its total repertoire of potential DNA-binding sites, based on sequence. This raises the question: Can ERα occupy these other potential binding sites in a different context? Ligands, splice variants, posttranslational modifications, and acquired mutations of ERα affect its conformation, which may alter chromatin interactions. To date, literature describes the DNA-binding sites of ERα (the ERα cistrome) in breast, endometrium, liver, and bone, in which the receptor mainly binds to enhancers. Chromosomal boundaries provide distinct areas for dynamic gene regulation between tissues, where the usage of enhancers deviates. Interactions of ERα with enhancers and its transcriptional complex depend on the proteome, which differs per cell type. This review discusses the biological variables that influence ERα cistromics, using reports from human specimens, cell lines, and mouse tissues, to assess whether ERα genomics in breast cancer can be translated to other tissue types.

Figure 1.. Tissues that are reported to provide genomic interplay between ERα and (putative) pioneer factors.

For references, see text.

Figure 2.. An overview of reported factors that influence the ERα cistrome.

Conformational cues (green zone) alter the conformation of ERα, thereby influencing its potential to interact with the chromatin and interaction partner(s), whereas environmental cues by the chromatin (white zone) affect the capacity of genomic regions to bind ERα. Some cues provide opportunities for ERα to bind throughout the body (white part of the circle), whereas other cues occur in a tissue-specific manner (purple part of the circle). PTM: Posttranslational Modification.