Recent Advances (2020–2025) in Estrogen and ER-Positive Breast Cancer: Receptor Signaling, Tumor Microenvironment, Endocrine Therapy Resistance and Innovative Treatment Strategies—A Comprehensive Review

Abstract

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.