HER-2 Signaling in Breast Cancer


Pathway Description

Breast cancer tumorigenesis is a multi-step process where each step correlates with one or more distinct mutations in regulatory genes. Based on the set of genes that are mutated, breast cancer can be classified into hereditary or sporadic forms. HER-2/ERBB2 (Human Epidermal Growth Factor Receptor-2) mutations play a role in sporadic breast cancer. HER-2 is overexpressed in 25-30% of breast cancer cases. Overexpression of HER-2 occurs either through gene amplification or transcriptional deregulation.HER-2 is a member of the EGFR family; the other members include - EGFR/HER-1, HER-3/ERBB3 and HER-4/ERBB4. These transmembrane receptors undergo dimerization and transphosphorylation upon ligand binding. HER-2 can homodimerize or form heterodimers with HER-1 or HER-3. Overexpression of HER-2 changes the composition of the HER family dimers, significantly increasing HER-2 homo- and heterodimers. Moreover, HER-2 containing dimers have a prolonged signaling ability and evade signal attenuation, thus exacerbating the effects of receptor overexpression.

HER-2 homodimers and heterodimers initiate various signaling pathways that influence breast cancer development. The most important oncogenic signaling function of the HER-2-HER-3 heterodimer is activation of the PI3K/AKT pathway. AKT mediates the downstream activation or inhibition of a number of proteins that are involved in cell growth, proliferation, survival, invasion and metastasis. The HER-2-HER-1 heterodimer mediates its signaling via Ras, PI3K and PLC-γ, resulting in cell hyperproliferation, cell migration and consequently tumorigenesis. Activation of HER-3 homodimers result in association with PAR6 and aPKC, which causes the dissociation of PAR3 from the active PAR3-PAR6-aPKC complex, leading to proliferation and protection against apoptosis. One important treatments for HER-2 positive breast cancer is Trastuzumab, a humanized monoclonal antibody binds the extracellular region of HER-2, causing de-activation, downregulation, and cell-killing by immune system effects. (Updated 09/04/2020)