ERBB2–Estrogen Receptor Interplay in Breast Cancer: Molecular Complexity, Tumor Heterogeneity, and Therapeutic Opportunities

Abstract

Human epidermal growth factor receptor 2 (HER2/ERBB2) is one of the most intensively investigated oncogenes in breast cancer research. Its amplification or over-expression defines a biologically aggressive subtype of breast cancer, historically associated with poor prognosis. Estrogen receptor (ER) signaling represents another dominant axis of breast carcinogenesis, governing tumor growth, differentiation, and response to endocrine therapy. Accumulating evidence demonstrates that ER and HER2 pathways are deeply interconnected through bidirectional molecular crosstalk, influencing tumor heterogeneity, therapeutic sensitivity, and resistance mechanisms. This review comprehensively synthesizes current knowledge on ERBB2 structure and signaling, ER biology, ER–HER2 crosstalk, receptor heterogeneity and discordance, clinical subtypes, and resistance to targeted therapies. In addition, emerging biomarkers and novel therapeutic vulnerabilities are discussed. A detailed understanding of ERBB2–ER interactions provides a rational framework for personalized and combinatorial treatment strategies in breast cancer.