This article was accepted into the corpus but its outbound wikilinks were never NER-processed — typical at the deepest BFS hop or when the run's entity cap was reached. No expansion funnel to show.
| HER2 | |
|---|---|
| Name | Human epidermal growth factor receptor 2 |
| Organism | Homo sapiens |
| Chromosome | 17q12 |
| Length | 1255 aa |
| Family | Receptor tyrosine kinase |
HER2
HER2 is a receptor tyrosine kinase encoded by the ERBB2 gene on chromosome 17q12. It functions as a member of the ErbB family of receptors and participates in cell signaling that controls proliferation, differentiation, survival, and migration. HER2 is clinically significant because of its role in several cancers, most notably breast cancer, and as a validated therapeutic target leading to major advances in oncology and targeted therapy.
HER2 is a transmembrane glycoprotein with an extracellular ligand-binding-like domain, a single-pass transmembrane helix, and an intracellular tyrosine kinase domain. In normal physiology it forms homo- and heterodimers with family members such as Epidermal growth factor receptor (EGFR), ErbB3, and ErbB4 to transduce signals through pathways including the PI3K–AKT and RAS–RAF–MEK–ERK cascades. Dimerization leads to autophosphorylation of key tyrosine residues that recruit adaptor proteins like GRB2, PIK3R1 and effectors such as SHC1, modulating processes in epithelial tissues including the mammary gland and the gastrointestinal tract. Post-translational modifications, membrane localization, and endocytic trafficking regulated by proteins like Cbl and the ESCRT machinery determine receptor turnover and signaling duration.
Amplification or overexpression of ERBB2 drives oncogenic signaling by increasing receptor density and promoting ligand-independent dimerization, contributing to uncontrolled proliferation, invasion, angiogenesis, and metastasis. ERBB2 alterations are oncogenic in breast, gastric, oesophageal, lung, and ovarian cancers and cooperate with genomic events involving TP53, PIK3CA, MYC, and loss of CDKN2A to shape tumor behavior. Gene amplification often arises through focal copy-number gain at 17q12 and is associated with chromosomal instability observed in tumors influenced by defects in BRCA1, BRCA2, and homologous recombination pathways. HER2-driven tumors display characteristic histopathologic features and can exhibit distinct metastatic patterns to organs such as bone, liver, and brain.
Clinical detection of ERBB2 status uses immunohistochemistry (IHC) to assess protein expression and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) to detect gene amplification. Guidelines from professional bodies like American Society of Clinical Oncology and College of American Pathologists define scoring systems (0 to 3+) and reflex testing algorithms to classify tumors as positive, equivocal, or negative for targeted therapy decisions. Next-generation sequencing panels and digital PCR assays detect ERBB2 mutations, insertions, and copy-number alterations alongside companion biomarkers such as PD-L1, MSI, and alterations in PIK3CA or PTEN that inform prognosis and combination strategies. Circulating tumor DNA assays and liquid biopsy platforms developed by companies and consortia like Foundation Medicine and academic centers enable noninvasive monitoring of ERBB2 amplification and emergent resistance mutations.
ERBB2 is the target of monoclonal antibodies (e.g., agents modeled after paradigms set by clinical programs at institutions like Dana-Farber Cancer Institute), antibody–drug conjugates, tyrosine kinase inhibitors (TKIs), and bispecific agents. Landmark therapies include humanized antibodies that block dimerization and engage immune effector functions, and antibody–drug conjugates that deliver cytotoxins selectively to ERBB2-expressing cells. Small-molecule TKIs developed by pharmaceutical companies and tested in trials at centers such as Memorial Sloan Kettering Cancer Center inhibit the kinase domain and have activity against certain ERBB2 mutations. Treatment strategies combine ERBB2-directed agents with chemotherapy, endocrine therapy in hormone receptor–positive tumors, and immune checkpoint inhibitors in trials organized by groups like SWOG and EORTC to improve outcomes.
Intrinsic and acquired resistance to ERBB2-targeted therapies arises via multiple mechanisms: secondary kinase domain mutations that alter drug binding, activation of bypass signaling through receptors such as MET or IGF1R, alterations in downstream effectors including activating mutations in PIK3CA or loss of PTEN, histologic transformation, and tumor microenvironmental influences mediated by stromal cells and immune checkpoints like CTLA-4 and PD-1. Heterogeneity of ERBB2 expression within tumors and selection of preexisting resistant clones under therapeutic pressure contribute to progression, including brain metastases protected by the blood–brain barrier. Comprehensive genomic profiling and serial biopsies coordinated by multidisciplinary teams at centers such as Johns Hopkins Hospital inform adaptive therapeutic decisions.
ERBB2 amplification or overexpression occurs in approximately 15–20% of invasive breast cancers and variable proportions of gastric and gastroesophageal junction cancers; prevalence estimates derive from large cohorts studied by consortia such as The Cancer Genome Atlas and registries like SEER. ERBB2-positive breast cancer historically carried a worse prognosis prior to targeted therapy but now has substantially improved survival with appropriate agents as demonstrated in randomized trials led by groups such as NSABP and BIG. Demographic, geographic, and socioeconomic factors influence testing rates and access to targeted therapies, with global initiatives by organizations like WHO and patient advocacy groups addressing disparities.
Active research areas include next-generation antibody–drug conjugates, bispecific antibodies, brain-penetrant TKIs, combinations with agents targeting PI3K/AKT/mTOR pathways, and strategies to prevent or overcome resistance informed by single-cell sequencing and patient-derived xenografts. Experimental models include cell lines (e.g., those established by laboratories at Cold Spring Harbor Laboratory), genetically engineered mouse models with conditional ERBB2 expression, patient-derived organoids, and syngeneic systems enabling immune-oncology studies. Large-scale efforts by consortia such as ENCODE and the International Cancer Genome Consortium integrate multi-omic datasets to identify biomarkers and synthetic lethal interactions for translational development.
Category:Oncogenes