Introduction Breast cancer is the most common cancer among

Introduction Breast cancer is the most common cancer among women worldwide, representing 30% of new cancer diagnoses. In addition, it is the second leading cause of cancer deaths among women [1]. With regard to the risk of breast cancer, proper diagnosis and stratification of tumors for individualized precision therapy is of the utmost importance. There is mounting evidence that human epidermal growth factor Oligomycin Complex synthesis 2 (HER2) plays an important role in the occurrence and development of breast cancer and the following treatment [2]. HER2-positive (gene amplification or protein overexpression) breast cancer is a particularly aggressive type that includes a higher mortality at early-stage, reduced time to relapse, and an increased incidence of metastases [3], [4] (Fig. 1). More importantly, its status may predict the response to chemotherapy and hormonal therapy. Indication of HER2 positivity is essential for treatment with anti-HER2 therapies, such as trastuzumab, pertuzumab and lapatinib, which have shown significant benefits in clinical practice [5], [6]. For this reason, the testing of HER2 status is important for the management of breast cancer patients.
Biological significance of HER2 In 1985, King et al. found that DNA from human breast cancer had amplification of the HER2 gene [7], and 2 years later, Slamon et al. reported that this amplification is important in the pathogenesis and progression of breast cancer [8]. Since then, HER2 gene amplification and the resultant protein overexpression have been correlated with important breast tumor cell proliferation and survival pathways. HER2 is a 185-kd transmembrane tyrosine kinase receptor belonging to the family of epidermal growth factor receptors (EGFRs). The corresponding HER2 (ERBB2) oncogene is located on the long arm of chromosome 17q12. HER1 (EGFR), HER3 (erbB3), and HER4 (erbB4) are the other members in the EGFR family. All these tyrosine kinase receptors are single subunit transmembrane glycoproteins, which are composed of three domains, including the extracellular ligand-binding domain, the transmembrane domain, and the intracellular tyrosine kinase catalytic domain. Upon ligand activation, the receptors undergo conformational changes that allow their homodimerization or heterodimerization, followed by transphosphorylation, which activates several intracellular signaling pathways, such as the phosphatidylinositol 3 kinase/Akt (PI3K/AKT) pathway, the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, and the phospholipase C (PLC) pathway [9]. Transcription factors activated by these pathways regulate many genes involved in cell proliferation, survival, differentiation, motility, and adhesion. To date, there is no known ligand for HER2 receptors to form homodimers, whereas HER2 relies on heterodimerization with other family members or homodimerization with itself when expressed at very high levels [10]. In the EGFR family, HER2 has the strongest catalytic kinase activity, and HER2-containing heterodimers have the strongest signaling activities [11], [12], thus playing a central role in those cellular processes. Therefore, aberrant expression of HER2 has been implicated in various cancers, especially in breast cancer.
HER2 amplification/overexpression in human breast cancer In general, normal breast tissue samples have shown no evidence of HER2 amplification and overexpression. However, in breast cancer tissues collected from patients, there are approximately 20% of breast cancers characterized by HER2 amplification/overexpression [13]. Among them, the HER2 gene may amplify 25–50 times and the HER2 protein may increase 40- to 100-fold [14]. As is well known, amplification of the HER2 gene is the major mechanism leading to protein overexpression, accounting for approximately 90% of such cases [15]. However, for a small proportion, protein overexpression may be due to transcriptional upregulation. Recent integrated proteogenomic research found that the protein expression may not be consistent with the level of gene or mRNA [16]. Currently, some believe that a protein used as a downstream regulator may be more reliable as a phenotype predictor.