Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications

Abstract

Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2.

Figure 1

Receptor homodimerization or heterodimerization leads to activation of downstream signaling pathways promoting cell growth, proliferation, and survival. HER2 exists in an open conformation making it the dimerization partner of choice among the family members. The PI3K/AKT axis (which is regulated by PTEN and involves other key effectors such as NFκB and mTOR) and the Raf/MAPK cascade are the two most important and most extensively studied downstream signaling pathways that are activated by the HER receptors. Ras is at the top of these cascades and acts as a self-inactivating signal transducer. A third important factor in the network is PKC, which is activated by PLC. As a result of these signaling pathways, different nuclear factors are recruited and modulate the transcription of different genes involved in cell-cycle progression, proliferation, and survival. EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; PLC, phospholipase C; PKC, protein kinase C; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; NFκB, nuclear factor κB; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase.

Figure 2

This image shows determination of HER2 status in 4 samples of breast tumor tissue. Samples (a) and (b) were analyzed by immunohistochemistry (IHC), while samples (c) and (d) were analyzed by fluorescence in situ hybridization (FISH). IHC detects protein and shows an increased expression of HER2 receptors, while FISH detects gene amplification. Sample (a) shows normal levels of HER2 protein expression, and sample (c) shows normal copy numbers of HER2 genes, while samples (b) and (d) show abnormal levels, respectively.