Intrinsic and Extrinsic Factors Governing the Transcriptional Regulation of ESR1

Abstract

Transcriptional regulation of ESR1, the gene that encodes for estrogen receptor α (ER), is critical for regulating the downstream effects of the estrogen signaling pathway in breast cancer such as cell growth. ESR1 is a large and complex gene that is regulated by multiple regulatory elements, which has complicated our understanding of how ESR1 expression is controlled in the context of breast cancer. Early studies characterized the genomic structure of ESR1 with subsequent studies focused on identifying intrinsic (chromatin environment, transcription factors, signaling pathways) and extrinsic (tumor microenvironment, secreted factors) mechanisms that impact ESR1 gene expression. Currently, the introduction of genomic sequencing platforms and additional genome-wide technologies has provided additional insight on how chromatin structures may coordinate with these intrinsic and extrinsic mechanisms to regulate ESR1 expression. Understanding these interactions will allow us to have a clearer understanding of how ESR1 expression is regulated and eventually provide clues on how to influence its regulation with potential treatments. In this review, we highlight key studies concerning the genomic structure of ESR1, mechanisms that affect the dynamics of ESR1 expression, and considerations towards affecting ESR1 expression and hormone responsiveness in breast cancer.

Keywords: Chromatin; Gene expression; Steroid receptor; Transcription.

Fig. 1

Kaplan–Meier plot showing the probability of relapse-free survival over time based on ESR1 expression levels (Affymetrix gene ID ESR1 205225 at). This plot was generated using the KM Plotter tool [9]. The patient cohort was restricted to ER+ breast cancer samples where ER status was derived from gene expression data (n = 3082). Samples were split into high and low expression groups relative to the median expression of ESR1 in the patient cohort [19]

Fig. 2

Diagram of the ESR1 gene (chromosome 6). aESR1 is approximately 300 kilobases and consists of several reported regulatory elements with some promoters utilized in a tissue-specific manner and eight exons. The nomenclature and numbering used in this diagram are based on NM_000125 and described by Kos et al. [49]. Diagram is not drawn to scale. bESR1 transcript variants differ by their 5′ UTR but are spliced to the same acceptor splice site shown in a. Shown is a screenshot of ESR1 variants on the UCSC Genome Browser (human assembly hg19) with ESR1 regulatory regions highlighted in light blue (chr6:151,968,286-152,147,486). c Genomic coordinates listed of key sites and regulatory elements of ESR1. Genomic coordinates start from the transcription start site (+ 1) and are based on the ESR1 cDNA sequence in NM_000125 and human genome assembly hg19 [51]

Fig. 3

Percent of invasive ductal carcinoma (IDC, n = 2440) and invasive lobular carcinoma (ILC, n = 373) cases with ESR1 genomic alterations. The data are derived from The Cancer Genome Atlas Research Network [Pan-Cancer Atlas; https://www.cancer.gov/tcga) and the METABRIC study [164, 165]

Fig. 4

Diagram of ESR1 with transcription factors and co-factors. Shown are transcription factors involved in repressing (yellow) or maintaining basal ESR1 expression (red). Transcription factors (TFs) that have dual repressive and activating roles are noted in yellow and red. TFs with unknown effects on ESR1 expression are noted in gray. Genomic coordinates shown above each regulatory element are based on the UCSC Genome Browser (human genome assembly hg19) [51]. Diagram is not drawn to scale