What Is HER2 Signaling And Overexpression In Breast Cancer
Invasive breast carcinomas have been found to over express the human epidermal growth factor receptor type 2/HER2/ErbB-2. Overexpression of the gene of HER2 is associated with reduction in overall survival rate as well as varied response to chemotherapy treatments. Hence, targeting HER2 overexpression is gaining importance where treatment for breast cancer is concerned.
Types of Human Epidermal Growth Factor Receptors (HER), Structure, and Functions
HER family includes four epidermal growth factor receptors, HER1, HER2, HER3, and HER4. They are also called as ErbB-1, ErbB-2, ErbB-3, and ErbB-4. These are transmembrane tyrosine kinase receptors and their functions include:
- Regulation of cell growth
- Cell survival
- Cellular responses etc.
The structure of each of these HER consist of:
- One extracellular binding domain
- Transmembrane lipophilic segment (HER3 does not have this)
- Intracellular tyrosine kinase domain
HER2 Signaling Pathway
- When the intracellular tyrosine domain inside the cell is phophorylated by dimerization or joining of two molecules of HER, cell proliferation and survival signaling begins.
- Dimerization can be between same molecules of HER (homodimerization) or different (heterodimerization).
- HER2 is the preferred dimerization partner for HER family members.
- The activate tyrosine end brings about a cascade of reactions intracellularly.
- First of all, the extracellular domain of HER2 is separated and it leaves behind p95, a membrane bound phosphorylated molecule that activates signal transduction pathways.
- It activates the lipid kinase phophoinositide 3-kinase (PI3 – K).
- Leading to phosphorylation of enzyme Ak transforming factor (Akt).
- Resulting in cell survival.
- Simultaneously, a guanine nucleotide exchange factor (SOS) activates rat sarcoma enzyme (RAS).
- RAS activates receptor activation factor (RAF).
- This in turn acts on MEK/mitogen extracellular signal kinase and mitogen activated protein kinase (MAPK).
- Resulting in cell proliferation.
- Signaling pathways also lead to production of vascular endothelial growth factor (VEGF) downstream.
- VEGF plays a part in angiogenesis.
Trastuzumab is a medication containing humanized monoclonal antibody that has been proved effective against HER2 dependent breast cancer. Trastuzumab reduces HER2 signaling by inhibiting dimerization of HER molecules. It unleashes Fc competent immune effector cells and various components of antibody dependent cell mediated cytotoxicity leading to death of cancerous cells.