Impact of p95HER2 Expression on Clinical Outcomes in HER2-Positive Breast Cancers: A Literature Review

Introduction

Human epidermal growth factor receptor 2 (HER2), is one of a family of 4 membrane tyrosine kinases (TKs), which was first discovered 25 years ago, and shown to be overexpressed in a human breast cancer cell (5) with its prevalence shown to be important in pathogenesis and disease progression in breast cancer patients (6).

The HER2 pathway was described in systems biology terms as a complex biological network composed of 3 layers: 1) An input layer of membrane receptors, alongside their ligands, whose function is to activate signal extracellular cascades, 2) A core system processing layer of protein kinases (PKs) who’s roles are signal transmission to the nucleus, followed by 3) An output layer of transcription factors, which function by regulating genes that effect various cellular functions, such as proliferation, migration, apoptosis as well as angiogenesis (1).

The input layer is composed of 4 membrane receptors/kinases (HER1–4) and their many ligands, including endothelin growth factor (EGF), transforming growth factor alpha (TGF-α), and heregulin. However, in breast cancer, HER2 is the dominant kinase receptor, overexpressed in 20% of cases (6). Upon ligand binding, the HER receptors undergo conformational changes that enable homo- or heterodimerization, followed by transphosphorylation of the receptors. HER2 does not have ligand- binding capabilities, but its open conformation allows for dimerization. When overexpressed, the activated form heterodimerizes with other HER members that have ligand-binding capabilities or undergoes homo-dimerization (1). This dimerization leads to the activation of the PI3K/AKT anti- apoptosis pathway (Figure 1), thereby stimulating the activation of transcription factors and exhibiting a proliferative, migratory, angiogenic, and differentiation cancer phenotypes. The estrogen receptor (ER) and the HER2 signaling pathways are the dominant drivers of cell proliferation and survival in most (85%) breast cancers (1).