HER 2: Biology, Detection, and Clinical Implications

The HER network, recently described in systems biology terms, is a robust redundant network comprised of an input layer of 4 membrane (M) tyrosine kinase (TK) receptors (HER1/EGFR-HER4) and multiple ligands [e.g., EGF, TGFα, amphiregulin (AR), and heregulins (HRG)]; a signal core processing layer involving a series of phosphorylation (e.g., activation of the PI3K/AKT, RAS/MEK/MAPK, and STATs kinase cascades) that transmit signals from the receptor layer to the output layer; and an output layer of transcription and coregulator factors (TF, CoReg) that function in the nucleus (N) to alter expression of genes regulating tumor cell proliferation, survival, and other characteristics of the malignant phenotype (, ). Upon ligand binding, the receptors undergo conformational changes that allow their homo- and heterodimerization and transphosphorylation, following by the activation of a plethora of downstream signaling cascades. HER2, which is gene-amplified and/or overexpressed in 20% of breast cancers, does not have a ligand, but exists in an open conformation exposing its dimerization domain; it can be activated by hetrodimerization with other ligand-bound HER members or by homodimerization when it is overexpressed. HER3 lacks the TK activity (X). Several drugs have been developed to block the HER2 pathway, most aimed at the receptor level. The HER2 monoclonal antibody trastuzumab is FDA-approved in both the metastatic and the adjuvant settings and the dual HER1–HER2 small molecule TK inhibitor lapatinib is FDA-approved in metastatic HER2+ breast cancers.

Publication

HER 2: Biology, Detection, and Clinical Implications. () Carolina Gutierrez, et al. Arch Pathol Lab Med. ;135(1):55-62. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions