The Human Epidermal Growth Factor Receptor 2 (HER2) is a protein that serves as a biomarker in oncology. This protein is found on the surface of certain cells, and when present at abnormally high levels, the condition is termed “overexpression.” Overexpression of HER2 drives the growth of several aggressive cancers, most notably in subsets of breast and gastric tumors. The presence of excessive HER2 fundamentally alters cell behavior, leading to uncontrolled proliferation and a more aggressive disease course. Understanding the cause of this overexpression is central to developing targeted therapies that have improved outcomes for patients with HER2-positive cancers.
The Normal Function of the HER2 Protein
In healthy cells, the HER2 protein functions as a specialized receiving antenna on the cell membrane. It is a member of the epidermal growth factor receptor family, which includes four related proteins. These receptors are classified as receptor tyrosine kinases, transmitting signals from outside the cell to the nucleus.
The normal role of the HER2 receptor is to respond to external growth factors, which instruct the cell to grow, divide, and repair itself. Unlike its relatives in the receptor family, HER2 does not require a specific growth factor to bind directly for activation. Instead, it is the preferred partner for forming pairs, or dimers, with other activated receptors in its family, ensuring cell growth occurs only when necessary.
The Genetic Error: HER2 Gene Amplification
The primary cause of HER2 overexpression in cancer is a specific, acquired genetic change called gene amplification. This is not a mutation inherited from parents, but rather a somatic error that occurs randomly within the DNA of a cell during its lifetime. The gene responsible for providing the instructions to make the HER2 protein is officially named ERBB2.
Gene amplification involves the cell mistakenly creating many extra copies of the ERBB2 gene within its nucleus. A normal cell typically has two copies of this gene. However, in HER2-positive cancer cells, the number of ERBB2 copies can increase dramatically, sometimes reaching dozens of extra copies. This overabundance of the gene is the fundamental cause of the problem.
With so many blueprints available, the cell machinery receives constant, overwhelming instructions to manufacture the protein. This results in the cell surface being covered with excessive numbers of HER2 receptors, known as overexpression. This massive increase in receptor density transforms a normally regulated cell into a cancer cell with a hyperactive growth engine.
How Overexpression Drives Tumor Growth
The consequence of having excessive HER2 receptors on the cell surface is the constant, uncontrolled activation of internal signaling pathways. Even in the absence of typical external growth factor signals, the sheer number of receptors causes them to spontaneously pair up with each other or with other receptors in the family. This pairing activates the internal tyrosine kinase domain of the receptor.
Once activated, the HER2 receptor launches a continuous cascade of internal signals that promote cell division and survival. These signals constantly tell the cell to proliferate, leading to the characteristic uncontrolled growth and rapid multiplication seen in aggressive tumors.
The hyperactivity of the HER2 pathway also provides a significant survival advantage by interfering with programmed cell death, or apoptosis. Furthermore, sustained signaling enhances the cell’s ability to break away from the primary tumor and invade surrounding tissues, increasing the potential for metastasis.
Testing for HER2 Status
Determining the HER2 status of a tumor is a standard procedure, as it directly informs the treatment strategy. Tissue samples obtained through a biopsy or surgery are analyzed to measure the amount of protein and the number of gene copies present using two main laboratory methods.
Immunohistochemistry (IHC)
IHC is typically the first test performed and measures the quantity of HER2 protein on the surface of the cancer cells. This method uses special antibodies that attach to the HER2 protein, producing a stain that pathologists score from 0 to 3+. A score of 0 or 1+ is considered HER2-negative, while a score of 3+ confirms protein overexpression and defines the tumor as HER2-positive.
Fluorescence In Situ Hybridization (FISH)
For cases where the IHC result is equivocal, meaning a score of 2+, or when definitive genetic confirmation is needed, a technique called FISH is used. FISH directly measures the number of ERBB2 gene copies inside the cell nucleus. By comparing the number of ERBB2 gene copies to a reference gene, FISH confirms whether the gene itself is amplified, providing definitive evidence for the underlying genetic error.