HER2 (Human Epidermal growth factor Receptor 2) is a transmembrane protein found on the surface of cells. It acts as a receiver for growth signals, spanning the cell membrane to relay external messages to the internal machinery. HER2 plays a direct part in regulating cell proliferation and survival, which is fundamental to normal tissue maintenance. In oncology, HER2 has become a major focus because its dysregulation drives aggressive tumor growth in several cancer types.
The Role of HER2 in Healthy Cell Growth
The HER2 protein is a member of the ErbB family of receptors, which includes three other related proteins. These receptors are designed to manage communication between the cell’s exterior and its nucleus, governing processes like cell division, differentiation, and tissue repair. HER2 is unique within this family because it does not have a known binding partner, or ligand, that activates it directly.
Instead, HER2 functions as the preferred partner for the other three ErbB family members. When another family member binds its specific growth factor, it pairs up with HER2 in a process called heterodimerization. This pairing activates the internal portion of the receptor complex, which acts as a tyrosine kinase. The activated kinase domain initiates a cascade of signals that travel into the cell, telling it to grow and divide in a controlled manner.
Under normal conditions, cells maintain a low and stable level of HER2 protein on their surface. This low expression is tightly regulated by cellular mechanisms, ensuring that growth signals remain balanced and appropriate for tissue needs. This controlled signaling is fundamental to healthy tissue turnover and maintenance.
How HER2 Overactivity Drives Cancer
The primary mechanism by which HER2 drives cancer is through a genetic event called gene amplification. This process involves the ERBB2 gene, which provides the blueprint for the HER2 protein, being duplicated multiple times within the cell’s DNA. As a result of this amplification, the cell produces an excessive number of HER2 proteins, leading to a condition known as overexpression on the cell surface.
In some cancer cells, this overexpression can result in up to two million HER2 receptors. This high concentration forces the HER2 proteins to pair up, forming homodimers and activating a constant, “always-on” growth signal even without an external growth factor. This unchecked signaling drives uncontrolled cell division and proliferation, which are the hallmarks of tumor growth.
HER2 overexpression is common in breast cancer (15% to 30% of cases) and in gastric and gastroesophageal junction cancers (10% to 30% of patients). Tumors driven by this overactivity tend to be more aggressive and historically had a poorer outlook compared to tumors without HER2 overexpression. The discovery of this specific pathway transformed treatment by providing a unique target for therapy.
Determining a Tumor’s HER2 Status
Determining a tumor’s HER2 status is crucial in cancer care because it dictates whether a patient will benefit from targeted anti-HER2 therapies. This status is assessed using tissue samples obtained from a biopsy or surgery. Testing aims to measure either the amount of HER2 protein on the cell surface or the number of ERBB2 genes within the cell.
The most common initial test is Immunohistochemistry (IHC), which uses antibodies to stain the HER2 protein on the cell surface. IHC results are reported on a semi-quantitative scale ranging from 0 to 3+. A score of 0 or 1+ is considered HER2-negative, while a score of 3+ indicates HER2-positive status, confirming a high level of protein overexpression.
When the IHC result is equivocal (a score of 2+), a secondary test is required for confirmation. This follow-up test is typically Fluorescence In Situ Hybridization (FISH). FISH is a molecular test that uses fluorescent probes to count the number of ERBB2 gene copies. A FISH-positive result confirms the tumor as HER2-positive, while a FISH-negative result reclassifies the tumor as HER2-negative.
Treatment Strategies Targeting HER2
The understanding that HER2-positive tumors depend on this hyperactive signaling pathway allowed for the development of targeted therapies. These treatments work by directly interfering with the HER2 protein or the downstream signals it generates. The monoclonal antibody Trastuzumab (Herceptin) was one of the first successful agents, designed to bind to the extracellular domain of the HER2 receptor.
By binding to the receptor, Trastuzumab physically blocks the HER2 protein from pairing up with other receptors, thereby inhibiting the runaway growth signal. This action suppresses the internal signaling pathways, such as PI3K/Akt and MAPK, which are responsible for cell proliferation and survival. Furthermore, Trastuzumab flags the cancer cell for destruction by the body’s own immune system, a process known as antibody-dependent cellular cytotoxicity (ADCC).
Newer targeted approaches include Antibody-Drug Conjugates (ADCs), which combine a monoclonal antibody like Trastuzumab with a potent chemotherapy drug. The antibody component delivers the chemotherapy agent directly to the HER2-overexpressing cancer cells, minimizing damage to healthy tissues. These targeted drugs are often used in combination with traditional chemotherapy or other inhibitors to block multiple growth pathways simultaneously, offering a personalized and highly effective strategy against HER2-driven cancers.