ESR1

Overview

ESR1 (Estrogen Receptor 1), also known as estrogen receptor alpha (ERα), is a nuclear receptor encoded by the ESR1 gene located on chromosome 6q25.1 in humans. As a ligand-activated transcription factor, ESR1 mediates the biological effects of estrogen by binding to estrogen response elements (EREs) in the promoters of target genes, thereby regulating cell proliferation, differentiation, and survival across multiple tissue types including the breast, uterus, ovary, bone, and liver. Upon estrogen binding, ESR1 undergoes conformational changes that promote receptor dimerization, coactivator recruitment, and transcriptional activation of downstream targets involved in cell cycle progression and apoptosis suppression. Beyond its canonical genomic signaling, ESR1 also participates in rapid non-genomic signaling cascades intersecting with the PI3K/Akt signaling pathway and JAK2/STAT3 signaling pathway, amplifying its influence over cellular behavior.

ESR1 holds central clinical importance because the majority of breast cancers — approximately 70–80% of diagnoses — are estrogen receptor-positive (ER+), making ESR1 the primary therapeutic target for endocrine therapies such as selective estrogen receptor modulators (SERMs), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). Activating mutations in ESR1, particularly in the ligand-binding domain, frequently emerge under the selective pressure of hormone-based treatments and are a major mechanism of acquired endocrine resistance in advanced breast cancer. Beyond oncology, ESR1 is implicated in reproductive disorders including polycystic ovary syndrome (PCOS) and endometriosis, as well as in metabolic and inflammatory conditions, underscoring its broad physiological relevance.

Focus of Latest Publications

Recent publications have examined ESR1 as a target in diverse computational and experimental contexts, most often in cancer and metabolic toxicity studies. In a network pharmacology and molecular docking analysis of the polyherbal nutraceutical Vernolac, ESR1 emerged as one of 14 hub nodes among predicted cancer-related targets, alongside Akt1, BCL2, CASP3, EGFR, and STAT3. The study linked Vernolac phytochemicals such as thymoquinone, quercetin, nigellidine, α-hederin, and carvacrol to multi-target anticancer activity, with enrichment across apoptosis, inflammation, oxidative stress, immune modulation, and cell proliferation pathways.

ESR1 was also identified as a critical regulatory hub in a systems toxicology study of per- and polyfluoroalkyl substances (PFAS) and gestational diabetes mellitus. Using epidemiological measurements, molecular docking, simulations, and mouse exposure experiments, the authors reported that PFPeA and PFTrDA were associated with altered glucose measures and hepatic metabolic dysfunction. ESR1 and SIRT1 were highlighted as key nodes linking PFAS exposure to disrupted lipid metabolic and nuclear receptor signaling networks, including PPAR, AMPK, FoxO, and PI3K-Akt pathways, with docking suggesting stable interactions between PFAS and these targets.

In environmental carcinogenesis research, ESR1 was one of six high-affinity targets identified for di-(2-ethylhexyl) terephthalate (DOTP) in an integrated multi-omics study of breast cancer progression. Molecular docking implicated ESR1, together with PIK3CA, PTPN11, PPARG, PTGS2, and MAPK1, and experimental validation showed that DOTP promoted tumor cell proliferation and increased ESR1 protein levels in a concentration-dependent manner. The study proposed interference with proliferation, transcriptional regulation, and carcinogenic signaling, particularly the PI3K-Akt-mTOR pathway, as a possible mechanism.

ESR1 also appeared in a network pharmacology analysis of acute liver injury, where it was among four hub genes identified from hepatoprotective monomers. Although JUN was the only consistently upregulated gene across transcriptomic datasets and was the main validated target, ESR1 was retained as part of the candidate hub set, indicating a possible role in the broader target network. In addition, a recent report on the approval of vepdegestrant noted its clinical relevance for patients with ESR1-mutant advanced breast cancer, underscoring ESR1 as an established therapeutic target in hormone-resistant disease.

Key Publications

• NEWJul A network pharmacology-based approach and molecular docking study to explore the therapeutic potential of a nutraceutical formula (Vernolac) in the treatment of cancer. (PloS one, 2026, PMID 42384725): "Protein-protein interaction analysis using STRING and Cytoscape revealed fourteen key hub nodes, including AKT1, BCL2, CASP3, CTNNB1, EGFR, ESR1, GAPDH, HSP90AA1, HSP90AB1, IL6, JUN, SRC, STAT3, and TNF."
• May Per- and polyfluoroalkyl substances are associated with gestational diabetes and perturb hepatic metabolic regulatory networks: Convergent epidemiological, computational, and experimental evidence. (Ecotoxicology and environmental safety, 2026, PMID 42208379): "Estrogen receptor 1 (ESR1) and sirtuin 1 (SIRT1) were identified as critical regulatory hubs linking PFAS exposure to metabolic dysfunction."
• May Approval of First PROTAC Opens New Era for Targeted Protein Degradation. (Cancer discovery, 2026, PMID 42137912): "For patients with ESR1-mutant advanced breast cancer, it offers a new therapeutic option after standard hormone-based regimens have failed."
• May Exploration of Potential Core Targets for Acute Liver Injury Based on a Novel Network Pharmacology Strategy Integrating the Common Efficacy and Mechanisms of Active Monomers. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42007886): "A total of 186 active monomers and four hub genes (JUN, STAT3, ESR1, and CTNNB1) were identified."
• May Di-(2-ethylhexyl) terephthalate promotes breast cancer progression: Multi-omics integrated experimental validation. (Chemico-biological interactions, 2026, PMID 41780785): "Subsequently, we used molecular docking to identify six carcinogenic targets with high affinity for DOTP (PIK3CA, PTPN11, ESR1, PPARG, PTGS2, and MAPK1)."
• May Guilu Erxian Glue combined with Wuzi Yanzong Pill attenuates granulosa cell apoptosis and ameliorates cyclophosphamide-induced diminished ovarian reserve via the lncRNA NEAT1/miR-204-5p/ESR1 axis. (Journal of ethnopharmacology, 2026, PMID 41616885): "the lncRNA NEAT1/miR-204-5p/ESR1 axis."