HER2: biology, detection, and clinical implications

Abstract

Context: HER2 is a membrane tyrosine kinase and oncogene that is overexpressed and gene amplified in about 20% of breast cancers. When activated it provides the cell with potent proliferative and antiapoptosis signals and it is the major driver of tumor development and progression for this subset of breast cancer. When shown to be overexpressed or amplified by appropriate methods, HER2 is a valuable treatment target.

Objectives: To review the basic biology of the HER2 signaling network, to discuss various approved methods for its detection in clinical specimens, and to describe the impressive results of therapies targeting HER2.

Data sources: Selected literature searchable on PubMed as well as older studies revealed by the literature review were reviewed.

Conclusion: HER2 is an important member of a complex signaling network and when gene amplified, it results in an aggressive subtype of breast cancer. Patients with tumors found to overexpress HER2 protein or to be amplified for the gene are candidates for therapy that significantly reduces mortality.

Figure 1. The HER signaling network and HER2-targeted therapy in breast cancer

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 (8, 12). 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.

Figure 2

HER2 immunohistochemistry Scoring performed by the ASCO/CAP guidelines. 20x magnification. A. 1+; B. 2+; C. 3+ (Using the 4B5 rabbit monoclonal antibody, Ventana Medical Systems, Inc., Tucson, AZ)

Figure 2

HER2 immunohistochemistry Scoring performed by the ASCO/CAP guidelines. 20x magnification. A. 1+; B. 2+; C. 3+ (Using the 4B5 rabbit monoclonal antibody, Ventana Medical Systems, Inc., Tucson, AZ)

Figure 2

HER2 immunohistochemistry Scoring performed by the ASCO/CAP guidelines. 20x magnification. A. 1+; B. 2+; C. 3+ (Using the 4B5 rabbit monoclonal antibody, Ventana Medical Systems, Inc., Tucson, AZ)

Figure 3

A. HER2 gene amplification using FISH by PathVysion (Vysis, Abbott Laboratories, Abbott Park, IL, USA), photo provided by Clarient,Inc.,Aliso Viejo, CA. B, C, D, HER2 gene amplification by Ultraview SISH Detection Kit (Ventana Medical Systems, Inc., Tucson, AZ); B. Chromosome 17 probe; C. HER2 probe not amplified; D. HER2 probe amplified.

Figure 3

A. HER2 gene amplification using FISH by PathVysion (Vysis, Abbott Laboratories, Abbott Park, IL, USA), photo provided by Clarient,Inc.,Aliso Viejo, CA. B, C, D, HER2 gene amplification by Ultraview SISH Detection Kit (Ventana Medical Systems, Inc., Tucson, AZ); B. Chromosome 17 probe; C. HER2 probe not amplified; D. HER2 probe amplified.

Figure 3

A. HER2 gene amplification using FISH by PathVysion (Vysis, Abbott Laboratories, Abbott Park, IL, USA), photo provided by Clarient,Inc.,Aliso Viejo, CA. B, C, D, HER2 gene amplification by Ultraview SISH Detection Kit (Ventana Medical Systems, Inc., Tucson, AZ); B. Chromosome 17 probe; C. HER2 probe not amplified; D. HER2 probe amplified.

Figure 3

A. HER2 gene amplification using FISH by PathVysion (Vysis, Abbott Laboratories, Abbott Park, IL, USA), photo provided by Clarient,Inc.,Aliso Viejo, CA. B, C, D, HER2 gene amplification by Ultraview SISH Detection Kit (Ventana Medical Systems, Inc., Tucson, AZ); B. Chromosome 17 probe; C. HER2 probe not amplified; D. HER2 probe amplified.