Novel estrogen-responsive genes (ERGs) for the evaluation of estrogenic activity

Abstract

Estrogen action is mediated by various genes, including estrogen-responsive genes (ERGs). ERGs have been used as reporter-genes and markers for gene expression. Gene expression profiling using a set of ERGs has been used to examine statistically reliable transcriptomic assays such as DNA microarray assays and RNA sequencing (RNA-seq). However, the quality of ERGs has not been extensively examined. Here, we obtained a set of 300 ERGs that were newly identified by six sets of RNA-seq data from estrogen-treated and control human breast cancer MCF-7 cells. The ERGs exhibited statistical stability, which was based on the coefficient of variation (CV) analysis, correlation analysis, and examination of the functional association with estrogen action using database searches. A set of the top 30 genes based on CV ranking were further evaluated quantitatively by RT-PCR and qualitatively by a functional analysis using the GO and KEGG databases and by a mechanistic analysis to classify ERα/β-dependent or ER-independent types of transcriptional regulation. The 30 ERGs were characterized according to (1) the enzymes, such as metabolic enzymes, proteases, and protein kinases, (2) the genes with specific cell functions, such as cell-signaling mediators, tumor-suppressors, and the roles in breast cancer, (3) the association with transcriptional regulation, and (4) estrogen-responsiveness. Therefore, the ERGs identified here represent various cell functions and cell signaling pathways, including estrogen signaling, and thus, may be useful to evaluate estrogenic activity.

A New Culture Model for Enhancing Estrogen Responsiveness in HR+ Breast Cancer Cells through Medium Replacement: Presumed Involvement of Autocrine Factors in Estrogen Resistance

“…ER activity was measured using an estrogen response element (ERE) reporter. As expected, E2 treatment considerably increased the activity and target gene expression of ER under EXC in MCF-7, in contrast to MTN (Figure 7A,B) [35]. These results reveal that EXC enables E2 to increase ERα activity, which in turn promotes cell proliferation.…”

Precision unveiled: Synergistic genomic landscapes in breast cancer—Integrating single‐cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics

“…This molecule orchestrates the differentiation of myeloid‐derived suppressor cells (MDSC), facilitating breast cancer progression, 37 instigating tumor‐associated macrophages, driving mammary vascular proliferation, 38 and promoting paracrine‐mediated tumor metastasis 39 . CTSD, a lysosomal protease, 40 serves as a negative prognostic marker for breast cancers, including triple‐negative subtypes, 41,42 and is associated with tumor metastasis 43 . HNRNPR, with its oncogenic tendencies, mediates tumor growth and spread via the HnRNPR‐CCNB1/CENPF axis, 44 with hypomethylation correlating with tumor proliferation and metastasis 45 .…”

Cholesterol de novo biosynthesis: a promising target to overcome the resistance to aromatase inhibitors in postmenopausal patients with estrogen receptor-positive breast cancer

“…This finding could appear unexpected given the specific mechanism of action of letrozole, which inhibits the aromatase by competitively binding to the heme of the cytochrome P450 of the enzyme. However, because some of these genes (especially HMGCR and FDPS) [27,28] are regulated by estrogen through a functional estrogen response element (ERE) in the promoter region, the decrease in the expression level observed in responsive tumors can be ascribed to the inhibition of the aromatase activity Figure 6. Biplots visualizing the relationship among the genes downregulated by the letrozole treatment ("cholesterol") and the genes involved in cell cycle control ("proliferation") in responsive and nonresponsive tumors.…”