The term HER2/neu refers to a protein and the gene that provides the instructions for making it. The protein is formally known as Human Epidermal growth factor Receptor 2 (HER2), and the corresponding gene is ERBB2. This receptor is part of a family of four related proteins that sit on the surface of human cells. Its status—whether normal or overexpressed—is a determining factor in guiding personalized medicine for several cancer types.
The Role of HER2 in Healthy Cells
The HER2 protein is a receptor found on the outer membrane of many healthy human cells. It is encoded by the ERBB2 gene and functions as a molecular antenna to receive external signals. Under normal conditions, HER2 regulates fundamental cellular processes like growth, division, and repair.
HER2 is unique because it does not require a specific external growth factor (ligand) to activate it. Instead, it pairs with other members of the Epidermal Growth Factor Receptor (EGFR) family (HER1, HER3, or HER4) to form a heterodimer. This pairing initiates a signaling cascade inside the cell that promotes cell survival and proliferation.
HER2 Amplification and Cancer Progression
Problems arise when the ERBB2 gene is copied too many times, a genetic abnormality known as gene amplification. This amplification leads to protein overexpression, resulting in an abnormally high number of HER2 receptors on the cell surface. The excess HER2 proteins form pairs, or dimers, much more easily, even without the involvement of other family members.
This excessive dimerization results in continuous, uncontrolled signaling inside the cell, trapping the cell’s growth mechanism in the “on” position. The constant activation of downstream pathways, such as PI3K/Akt/mTOR and MAPK, drives rapid cell division. Cancers characterized by this overexpression are called HER2-positive and are frequently observed in tumor types like breast and gastric cancers.
High levels of HER2 signaling often correlate with aggressive tumor behavior and a higher potential for metastasis. This occurs because the overactive HER2 pathways promote cell motility and survival. HER2-positivity acts as a predictive marker, indicating that while the tumor may grow rapidly, it is also susceptible to specific therapies.
Identifying HER2 Status Through Testing
Determining a tumor’s HER2 status is necessary before treatment, as it dictates the use of targeted drugs. The diagnostic process typically begins with analyzing a tissue sample from a biopsy using Immunohistochemistry (IHC). IHC measures the amount of HER2 protein present on the surface of the cancer cells.
The IHC test uses specialized antibodies linked to a colored marker that binds to the HER2 protein. Pathologists score the result on a scale from 0 to 3+. A score of 0 or 1+ indicates low or absent HER2 protein and is considered HER2-negative. A score of 3+ signifies high protein overexpression, designating the tumor as HER2-positive and qualifying it for targeted treatment.
When the IHC result is 2+, the result is considered “equivocal” or unclear. In this scenario, a second test, Fluorescence In Situ Hybridization (FISH), is required for confirmation. FISH is a molecular genetic test that directly measures the number of copies of the ERBB2 gene inside the cell nucleus. This test uses fluorescent probes to count the gene copies and determine if gene amplification has occurred.
Targeted Therapies for HER2-Positive Cancers
The discovery of HER2-positive cancers led to the development of targeted therapies that interfere with the overactive HER2 signaling pathway. These treatments selectively target cancer cells while minimizing damage to healthy cells. One major class of therapy is monoclonal antibodies, which are laboratory-made proteins mimicking the body’s natural immune response.
Monoclonal antibodies, such as trastuzumab and pertuzumab, bind to the extracellular domain of the HER2 receptor. Trastuzumab blocks the growth signal and alerts the immune system to destroy the cancer cell, a process known as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). Pertuzumab binds to a different site, preventing HER2 from pairing with other EGFR family members and complementing trastuzumab’s action.
Antibody-Drug Conjugates (ADCs) link a monoclonal antibody to a potent chemotherapy drug. Drugs like trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) use the HER2 antibody as a delivery vehicle. Once the antibody binds to the receptor, the complex is internalized, and the chemotherapy payload is released directly inside the tumor cell. This mechanism delivers a highly concentrated dose of chemotherapy, limiting systemic side effects.
Small molecule tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, represent a third class of treatment. These drugs pass through the cell membrane and act inside the cell, blocking the activity of the HER2 receptor’s internal signaling domain. By inhibiting this tyrosine kinase activity, TKIs prevent the receptor from activating the downstream pathways that drive cell growth.