Aug 2026· Gene· Vol 1012, pp.
150376
· 0 citations· 119 references
Medicine
TL;DR
Overall, therapeutic progress increasingly depends on matching ERα-directed interventions to dynamic biomarkers, resistance mechanisms, treatment history, and tolerability rather than assuming uniform benefit across ER-positive disease.
Abstract
Estrogen receptor alpha (ERα) is central to breast-cancer initiation, progression, and endocrine resistance. This narrative review uses a transparent, non-systematic search of peer-reviewed English-language literature published from 2017 through 2025 to integrate ERα structure and isoforms, genomic and non-genomic signaling, post-translational regulation, tumor-microenvironment interactions, heterogeneity, and therapeutic development. The synthesis distinguishes mechanistic, preclinical, and clinical evidence and highlights areas of uncertainty. ESR1 ligand-binding-domain mutations are rare in untreated primary disease but are enriched after endocrine selection in metastatic disease; emerging oral SERDs, ER-directed PROTACs, and biomarker-matched pathway combinations show heterogeneous results across overall and molecularly defined populations. ER-low disease remains a clinically important category requiring confirmation of pathology, integration of tumor biology and disease setting, and individualized use of endocrine and chemotherapy-based strategies. Overall, therapeutic progress increasingly depends on matching ERα-directed interventions to dynamic biomarkers, resistance mechanisms, treatment history, and tolerability rather than assuming uniform benefit across ER-positive disease.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor clinical outcomes. Owing to the absence of estrogen receptors, progesterone receptors, and Human Epidermal Growth Factor Receptor 2 (HER2) expression, TNBC shows limited responsiveness to conventional endocrine and targeted therapies. This subtype exhibits strong heterogeneity, a high propensity for metastasis, and a tendency to develop acquired drug resistance. Its survival and progression largely rely on non-classical signaling pathways, including Epidermal growth factor receptor (EGFR), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), and Notch, which collectively impose substantial challenges to clinical management. In recent years, protein post-translational modifications—particularly ubiquitination and ubiquitin-like modifications—have emerged as key mechanisms governing TNBC malignant progression. This review systematically summarizes the stage-specific regulatory roles of ubiquitination during TNBC initiation, progression, and therapeutic resistance. These mechanisms include modulation of tumor stemness, epithelial–mesenchymal transition, DNA damage repair, ferroptosis, and immune evasion through the regulation of critical proteins such as Toll-like receptor 4/Nuclear factor kappa-B (TLR4/NF-κB), Twist family bHLH transcription factor 1 (TWIST1), Poly (ADP-Ribose) Polymerase 1 (PARP1), Programmed death-ligand 1 (PD-L1), and Glutathione Peroxidase 4 (GPX4). In addition, ubiquitin-like modifications (including small ubiquitin-like modifier (SUMOylation), Neural precursor cell expressed developmentally downregulated protein 8 (NEDDylation), and Interferon-stimulated gene (ISGylation)) function synergistically in maintaining genome stability, transcriptional regulation, and immunological processes. Furthermore, this review highlights the translational potential of targeting ubiquitination pathways in TNBC, covering the applications, advantages, and limitations of immune checkpoint inhibitors, Poly ADP-ribose polymerase (PARP) inhibitors, antibody–drug conjugates, and combination treatment strategies. Finally, it outlines future research directions, such as developing a TNBC-specific ubiquitinome landscape, creating highly selective E3 ligase or deubiquitinase inhibitors, and integrating multi-omics with artificial intelligence technologies. These advances are expected to provide a theoretical foundation and translational insights for precision interventions targeting protein homeostasis in TNBC.
Yongpan Wang, Wei-Qiang Huang, Qizhuan Lin et al.· Oncology Research· 0 citations
Breast cancer remains one of the most common cancers in women, in which the majority of cases exhibit a hormone receptor-positive subtype. Although several treatment options are available for patients with this subtype, first-line therapies mainly rely on the patient’s sensitivity to endocrine therapy. Therapy resistance, which frequently develops over the treatment course, remains a key obstacle for clinical intervention. Efforts are currently underway to elucidate additional therapeutic targets to restore endocrine therapy sensitivity and treat hormone receptor-positive breast cancer. Here, we summarize work surrounding the sigma-2 receptor (σ2R) and its potential role in endocrine therapy resistance pathways, including PI3K-mTOR signaling and cholesterol metabolism. Although σ2R was pharmacologically characterized decades ago, its molecular identity remained elusive until 2017, when transmembrane protein 97 (TMEM97) was established as the sigma-2 receptor. TMEM97/σ2R is highly expressed in hormone receptor-positive breast cancer and its RNA expression levels are associated with endocrine resistance. High expression of TMEM97/σ2R elevates estrogen receptor activities and confers breast cancer cells with increased resistance to endocrine therapy via enhanced mTOR signaling. Given the role of TMEM97 in cholesterol homeostasis, understanding the connections between TMEM97/σ2R, breast cancer, and cholesterol regulation may reveal new pathways to aid in the development of targeted therapies. Evidence remains preclinical, and further investigation is needed to confirm hypothesized pathways involving TMEM97/σ2R in breast cancer endocrine resistance.
Lucy M. Fitzgibbons, Yuan-Qin Zhang, Xiang-Wei Fang et al.· Kinases and Phosphatases· 0 citations
Abstract Estrogen receptor-positive (ER+) breast cancer accounts for 70–80% of all invasive breast malignancies worldwide and remains the dominant subtype driving rising global breast cancer incidence, representing a major clinical burden in China with a 2.84% annual age-standardized incidence increase. Endocrine therapy serves as the cornerstone intervention for ER+ disease, yet primary and acquired drug resistance severely undermine long-term therapeutic efficacy, creating an urgent demand for systematic integration of updated mechanistic and translational evidence. This comprehensive review systematically summarizes high-quality literature published from 2020 to 2025, focusing on estrogen biosynthesis and metabolic dysregulation, dual genomic/non-genomic estrogen receptor signaling mediated by ERα, ERβ and GPER1, epigenetic regulatory networks, and bidirectional crosstalk between estrogen signaling and the breast tumor microenvironment (TME). We further dissect multi-layered mechanisms underlying endocrine resistance, including ESR1 mutations/fusions, aberrant activation of PI3K/AKT/mTOR and MAPK pathways, dysregulated ER co-regulators, and expansion of breast cancer stem cells. Current mainstream endocrine agents (AIs, SERMs, SERDs), CDK4/6 inhibitors, and innovative combinatorial regimens targeting drug-resistant clones are also thoroughly discussed. Core consensus from the included literature indicates that ERα acts as a major oncogenic driver while ERβ exerts tumor-suppressive functions; GPER1-mediated non-genomic signaling frequently fuels metastasis and tamoxifen resistance. ESR1 genetic alterations and TME immunosuppressive remodeling constitute the two leading causes of therapeutic failure. Emerging therapeutic candidates, including GPER1 antagonists, ESRRA modulators and epigenetic regulators, have only demonstrated context-dependent anti-endocrine resistance effects in preclinical cell and animal models; substantial contradictory mechanistic data and a complete lack of large-scale human clinical trials restrict their immediate clinical application. Throughout this review, we systematically stratify all interventions by evidence strength to distinguish standard clinical regimens from purely experimental preclinical strategies and thoroughly discuss unresolved limitations and conflicting research observations for each investigational target. Translational approaches with robust clinical validation include liquid biopsy for real-time ESR1 mutation surveillance and standardized lifestyle preventive interventions for high-risk groups, while single cell/spatial multi-omics and gut microbiome modulation remain exploratory analytical or preventive tools with unresolved technical and population variability barriers.
Jia-Xin Zhao, Donghai Li, Shaofeng Yang et al.· Cancer Management and Resear...· 0 citations
Abstract Prostate cancer is the second most common cause of cancer in men worldwide, and first-line therapies for metastatic disease include androgen deprivation therapy and androgen receptor pathway inhibitors, in addition to chemotherapy for selected patients. Although these strategies improve patient prognosis, progression to castration-resistant prostate cancer and therapeutic resistance remain clinically significant. In this review, we will explore published and new evidence of the expression and function of estrogen receptors (ERs) ERα and ERβ, as well as their variants, and the G protein-coupled estrogen receptor (GPER) in normal prostate gland, during development and adulthood and in prostate cancer cell lines. Consistent with these findings, studies from the literature have demonstrated that ERα, ERβ, and GPER are expressed in a cell-specific manner in the normal prostate gland. In the androgen-independent prostate cancer cells PC-3 (derived from bone metastasis) and DU-145 (brain metastasis), used in vitro and in xenograft implants as castration-resistant prostate cancer models, ERα and ERβ are present at transcript and protein levels, as well as the GPER. Importantly the presence of ERα36 splice variant is also detected in prostate cancer cells. Although the exact contributions of these modifications to prostate cancer advancement and treatment outcomes remain under investigation, the absence of selective inhibitors for the resulting ER variant proteins restricts deeper inquiry. Developing such targeted agents is crucial to uncovering variant biology in both healthy and malignant tissues, evaluating their therapeutic value in preclinical settings, and ultimately guiding clinical management.
D. S. Souza, Camila Rebelo Morgado Costa, Larissa Thainá Brito Dias et al.· Journal of the Endocrine Soc...· 0 citations
BACKGROUND
Folate receptor-α is an established therapeutic target in ovarian cancer and identifies candidates for mirvetuximab soravtansine. However, co-expression patterns between folate receptor-α and other actionable biomarkers, and their therapeutic implications, remain incompletely characterized.
METHODS
We conducted a single-institution cohort study of 110 patients with platinum-resistant ovarian cancer treated with mirvetuximab soravtansine (2019-2025). Tumor biomarkers were assessed using immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. Co-expression among 10 biomarkers, including folate receptor-alpha, estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2, BRCA, homologous recombination/loss of heterozygosity, programmed death-ligand 1, claudin-6, and tumor mutational burden, were evaluated using Jaccard similarity indices, Cohen's kappa statistics, and correlation analyses. Exploratory progression-free survival and overall survival analyses were performed by folate receptor-α and estrogen receptor sub-groups.
RESULTS
Folate receptor-α expression was high in 80% of tumors and intermediate/low in 20%. Co-expression analyses demonstrated largely independent biomarker patterns, reflecting biological heterogeneity. A hormone receptor-associated cluster emerged, including strong co-expression between folate receptor-α and estrogen receptor (Jaccard = 0.76), and moderate overlap between estrogen receptor and claudin-6 (0.62), programmed death-ligand-1 and estrogen receptor (0.56), and programmed death-ligand-1 and folate receptor-α (0.50). Survival outcomes were comparable between folate receptor-α-high and folate receptor-α-intermediate/low tumors. Among folate receptor-α-high tumors, estrogen receptor expression (≥10%) did not meaningfully stratify progression-free or overall survival outcomes.
CONCLUSIONS
Biomarker co-expression in advanced ovarian cancer demonstrates substantial heterogeneity, with patterns that may inform future biomarker-guided treatment combinations and sequencing strategies. Prospective validation is needed to refine multi-marker frameworks and determine whether biologically driven treatment approaches based on co-expression biomarker patterns may have clinical utility. Exploratory analyses support further investigation of folate receptor-α as a potentially graded rather than strictly binary biomarker; however, these findings are hypothesis-generating.
E. Shachar, J. Silverstein, J. Gornbein et al.· International Journal of Gyn...· 0 citations
Abstract Objectives Estrogen receptor alpha (ERα) is thought to be a ligand-dependent transcription factor. Increasing number of data suggest that ERα is able to retain its transcriptional activity without stimulation by estrogen and therefore contributes to development of endocrine resistance in hormone receptor-positive cancers. The objective of this paper is to overview molecular mechanisms of ligand-independent activation of ERα and to address the clinical significance of these mechanisms. Methods A detailed literature review of recent experimental, translational and clinical studies has been performed with the aim of exploring molecular mechanisms of ligand-independent ERα activation, clinical significance of these mechanisms, and their application to molecular diagnostics and targeted therapy. Results There are several ways of maintaining transcriptional activity of ERα in the absence of estrogen ligand. They include ESR1 mutations and gene fusions, alterations in signaling pathways involving growth factor receptors, abnormalities in regulation by co-regulators, epigenetic rewiring, and post-translational modifications. These changes contribute to endocrine resistance and might explain the discordance between expression of ER determined by immunohistochemical staining and clinical response to endocrine therapy. Conclusion The recognition of signaling by ERα that is not ligand-dependent will lead to an expansion of knowledge about the estrogen receptor and the shortcomings of depending only on immunohistochemical ER status for decision making in treatment. It might be beneficial for the prediction of patients' sensitivity to endocrine treatment by adding molecular biomarkers related to the activity of the ERα.
G. Rathod, P. Parmar· Hormone Molecular Biology an...· 0 citations
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