her2

HER2, or human epidermal growth factor receptor 2, also designated ERBB2, is a member of the ErbB family of receptor tyrosine kinases. It encodes a transmembrane glycoprotein with an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. Unlike the other ErbB receptors, HER2 has no clearly identified direct ligand and is readily available to form dimers with other ErbB receptors, activating signaling pathways even in the absence of ligand.

Physiologically, HER2 participates in control of cell growth, differentiation, and survival. Activation occurs mainly through dimerization with other ErbB receptors, leading to autophosphorylation and stimulation of downstream signaling cascades, notably the PI3K/AKT and RAS/ERK pathways. Dimerization can be homodimeric or heterodimeric with EGFR/HER1, HER3, or HER4, and the pattern of dimerization influences signaling strength and cellular response.

In cancer, HER2 is amplified or overexpressed in a subset of tumors, most notably breast cancer, where about 15-20% of cases are HER2-positive. It also occurs in a smaller proportion of gastric and gastroesophageal junction cancers and other tumor types. HER2 status is a predictive biomarker for response to HER2-targeted therapies and a prognostic factor in some settings. Assessment is typically by immunohistochemistry (IHC) and/or in situ hybridization (FISH or CISH) to measure protein expression or gene amplification.

Therapies targeting HER2 have transformed outcomes for HER2-positive diseases. Treatments include monoclonal antibodies such as trastuzumab and pertuzumab, antibody-drug conjugates such as trastuzumab emtansine and trastuzumab deruxtecan, and small-molecule tyrosine kinase inhibitors such as lapatinib, neratinib, and tucatinib. Resistance and adverse effects remain clinical challenges, and ongoing research continues to optimize testing, sequencing, and combination strategies.