EstroGene database reveals diverse temporal, context-dependent and directional estrogen receptor regulomes in breast cancer

Abstract

As one of the most successful cancer therapeutic targets, estrogen receptor-α (ER/ESR1) has been extensively studied in decade-long. Sequencing technological advances have enabled genome-wide analysis of ER action. However, reproducibility is limited by different experimental design. Here, we established the EstroGene database through centralizing 246 experiments from 136 transcriptomic, cistromic and epigenetic datasets focusing on estradiol-treated ER activation across 19 breast cancer cell lines. We generated a user-friendly browser (https://estrogene.org/) for data visualization and gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, documentation-based meta-analysis revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. We defined temporal estrogen response metasignatures and showed the association with specific transcriptional factors, chromatin accessibility and ER heterogeneity. Unexpectedly, harmonizing 146 transcriptomic analyses uncovered a subset of E2-bidirectionally regulated genes, which linked to immune surveillance in the clinical setting. Furthermore, we defined context dependent E2 response programs in MCF7 and T47D cell lines, the two most frequently used models in the field. Collectively, the EstroGene database provides an informative resource to the cancer research community and reveals a diverse mode of ER signaling.

EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer

“…Similar to observations from EstroGene1.0 (35), publicly available data from studies performed after 2017 was for the most part generated using next-generation sequencing technologies, while 12 microarray was more prevalent in earlier studies (Fig. 1B).…”

“…Extending its predecessor, EstroGene1.0 (35), which focused solely on experiments analyzing treatment with estrogens. EstroGene2.0 encompasses transcriptomic and ER ChIP-seq profiling data from studies performed with a large number of different ER modulators in models of both endocrine therapy sensitive and resistant breast cancer cells.…”

ESR1fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes

“…The enrichment of a E2 related signature in Gou et al’s work compelled us to examine the expression levels of a cohort of up-regulated E2 responsive genes derived from T-47D RNAseq data that is publicly available through EstroGene (28). All four fusion constructs and the truncated fusion protein were enriched in the E2 signature emphasizing that ER fusions retain components of the canonical ER regulome.…”

“…To assess how ER fusions affect the transcriptome, we compared DEGs to previously reported estrogen response signatures. Our laboratory has recently established EstroGene, a database containing publicly available RNA sequencing, ChIP sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing data in breast cancer cell lines treated with vehicle control or estradiol at various dosages and durations (28). From this dataset, the top 10 percentile of estradiol regulated genes in T-47D cells (n=127) was utilized as an estrogen response signature.…”

“…Data visualization was performed using ggplot2 package (57). EstroGene (estrogene.org) is a curated collection of MicroArray analyses, RNAseq analyses, and ChIP-seq analyses (28).…”