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.
Competing Interest Statement
Tsinghua University paid the stipend of University of Pittsburgh-affiliated foreign scholar Yang Wu from Tsinghua University.
Footnotes
Financial Support, This work was supported by the Breast Cancer Research Foundation (AVL and SO]; Susan G. Komen Scholar awards (SAC110021 to AVL and SAC160073 to SO]; the Metastatic Breast Cancer Network Foundation [SO]; the National Cancer Institute (R01CA221303 to SO, R01256161 to AVL, F30CA250167 to MEY, R01CA251621 to MJS], the Fashion Footwear Association of New York, Magee-Women’s Research Institute and Foundation, The Canney Foundation, The M&E Foundation, and the Shear Family Foundation. SO and AVL are Hillman Fellows. ZL is supported by John S. Lazo Cancer Pharmacology Fellowship.
Conflict of Interest Disclosure Statement, Tsinghua University paid the stipend of University of Pittsburgh-affiliated foreign scholar Yang Wu from Tsinghua University.