Human cells contain proteins that manage fundamental processes, including growth and division. One of these is the Human Epidermal Growth Factor Receptor 2, or HER2. This protein is a receptor on the surface of cells that relays signals telling the cell to grow and divide. In a healthy cell, the production and activity of HER2 are carefully regulated for normal tissue development and repair.
This regulatory system can falter in some breast, stomach, and esophageal cancers. When control over the HER2 protein is lost, it can lead to aggressive and uncontrolled cell proliferation. This malfunction makes the status of HER2 a point of focus in diagnosis and treatment planning.
Defining HER2 Amplification
The instructions for building every protein in the body, including HER2, are encoded within genes. The specific gene responsible for producing the HER2 protein is known as ERBB2. This gene resides on chromosome 17, and under normal circumstances, every cell has two copies of it to provide the blueprint for the amount of HER2 protein required for its standard functions.
In some cancer cells, a genetic error called gene amplification occurs. This process involves the replication of a specific DNA segment numerous times, resulting in extra copies of a gene. When the ERBB2 gene is amplified, the cancer cell may contain dozens or even hundreds of copies instead of the standard two.
This genetic change occurs in approximately 15-20% of breast cancers. The presence of so many extra copies of the ERBB2 gene gives the cell a vastly increased capacity to produce the HER2 protein. This is not a mutation in the gene itself, but a dramatic increase in its quantity.
The consequences of this amplification are profound, setting the stage for the cell to behave abnormally. This alteration disrupts the normal checks and balances that govern cell division, priming the cell to produce an excessive amount of HER2 protein.
Understanding HER2 Overexpression
The direct consequence of HER2 gene amplification is protein overexpression. With hundreds of extra copies of the ERBB2 gene, the cell’s protein-making machinery goes into overdrive, translating those blueprints into a massive surplus of HER2 proteins. These proteins are then embedded into the cell’s surface, creating a dense field of receptors that far exceeds what is found on a normal cell.
These excess HER2 receptors do not remain dormant. When present in high numbers, they can become active without needing the usual external signals that trigger cell growth. The receptors can pair up with each other, a process called homodimerization, which switches them into a permanent “on” state. This sends a relentless stream of signals into the cell’s interior, constantly instructing it to grow and divide.
This continuous signaling drives the aggressive nature of HER2-positive cancers. The cells are no longer responding to the body’s controlled growth cues but are instead stimulated from within by their own overabundant receptors, leading to rapid tumor formation.
While amplification describes the genetic cause (too many gene copies), overexpression describes the tangible effect at the protein level (too many receptors sending growth signals). The two events are linked, with amplification being the underlying genetic abnormality and overexpression being its direct, growth-promoting result.
Testing Methods for HER2 Status
To determine if a cancer is driven by HER2, pathologists use laboratory tests on a tumor tissue sample obtained through a biopsy or surgery. These tests measure either the amount of HER2 protein on the cancer cells or the number of ERBB2 gene copies within them. The two primary methods are Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH).
Immunohistochemistry is a test that detects protein overexpression. In this procedure, the tumor tissue is exposed to antibodies that recognize and bind to the HER2 protein. A chemical dye attached to these antibodies then stains the cells, making the HER2 proteins visible under a microscope. The amount of staining is graded on a scale from 0 to 3+.
A score of 0 or 1+ is considered HER2-negative, while a 3+ score indicates significant HER2 protein overexpression and is classified as HER2-positive. A score of 2+ on an IHC test is considered equivocal or borderline. In these cases, a second, more definitive test is required to clarify the HER2 status, which is where FISH comes in.
The FISH test directly measures gene amplification by counting the number of ERBB2 genes. Fluorescent probes are used that are engineered to attach specifically to the ERBB2 gene. When viewed with a special microscope, these glowing probes can be counted. A result showing an average of more than four copies of the ERBB2 gene per cell is considered positive for amplification, resolving the ambiguity of a 2+ IHC result.
How HER2 Status Guides Cancer Treatment
The determination of a tumor’s HER2 status is an important step in developing a patient’s treatment plan. Cancers classified as HER2-positive have a specific biological vulnerability that can be exploited with targeted therapies. These treatments are designed to specifically interact with the HER2 protein, disrupting the growth signals that fuel the cancer.
Unlike traditional chemotherapy that affects all rapidly dividing cells, HER2-targeted therapies are more precise. A foundational drug in this class is trastuzumab (Herceptin). Trastuzumab is a monoclonal antibody that recognizes and binds to the extracellular portion of the HER2 receptor on the cancer cell’s surface, blocking it from sending growth signals into the cell.
Other targeted therapies have also been developed to combat HER2-positive cancers. Some drugs, known as antibody-drug conjugates, link a powerful cancer-killing agent directly to an antibody that seeks out the HER2 protein. This approach allows for the direct delivery of a toxic payload to the cancer cells. Another class of drugs, called kinase inhibitors, works inside the cell to block the downstream signaling activity that the HER2 receptor initiates.
The availability of these targeted treatments has dramatically improved outcomes for patients with HER2-positive breast cancer, which was once associated with a more aggressive disease course. Identifying a tumor as HER2-positive opens the door to these highly effective medicines, which can be used alone or in combination with chemotherapy.