HER2-positive cancer refers to the presence of an excessive amount of the Human Epidermal growth factor Receptor 2 protein on the surface of cancer cells. This designation functions as a biomarker used to identify a specific disease state. HER2 positivity is most frequently recognized in aggressive forms of breast and gastric cancers. Determining this status is a foundational step in modern oncology, as it directly influences the choice of targeted treatments for the patient.
The Normal Function of the HER2 Gene and Protein
The HER2 protein is a member of the ErbB family of receptors located on the cell membrane in healthy tissues. The gene that codes for this protein, called ERBB2, ensures a controlled, low number of HER2 receptors are available. These receptors act as receivers for external growth signals, regulating the cell’s processes of division, repair, and differentiation.
Unlike its family counterparts, the HER2 protein does not bind directly to a growth factor ligand to become active. Instead, it is the preferred partner for other ErbB family members, such as HER1 (EGFR) or HER3, forming a pair known as a heterodimer. This pairing initiates the cellular signal.
Once a heterodimer forms, the internal part of the receptor complex, which possesses tyrosine kinase activity, becomes activated. This activation involves the phosphorylation of specific amino acid residues, creating docking sites for various intracellular signaling molecules. This process allows the cell to respond appropriately to external cues, promoting necessary cell growth or repair in a controlled manner.
Genetic Amplification: The Mechanism of HER2 Positivity
The fundamental cause of HER2-positive cancer is a genetic error known as gene amplification. Gene amplification is a process where a specific region of the cell’s DNA is mistakenly copied multiple times. In HER2-positive cancer, the ERBB2 gene, located on chromosome 17, undergoes this duplication.
This error is distinct from a simple gene mutation, which is a change in the sequence of the DNA letters. Instead, the cell ends up with many extra copies of the entire ERBB2 gene, leading to an increased gene copy number. This amplification is a somatic alteration, meaning it is acquired during a person’s lifetime and is present only in the tumor cells, not inherited.
The consequence of having extra copies of the ERBB2 gene is the overproduction of the corresponding HER2 protein. The cellular machinery transcribes the excess DNA into an abundance of messenger RNA (mRNA), which is then translated into many more HER2 proteins. This results in the overexpression of the protein, meaning an excessive density of HER2 receptors becomes embedded in the cell’s membrane.
The result of this amplification is the presence of hundreds of thousands, or even millions, of HER2 receptors on the surface of each cancer cell. This high quantity fundamentally alters the cell’s signaling dynamics. The presence of these receptors is the molecular characteristic that defines a cancer as HER2-positive.
Cancers Where HER2 Overexpression is Common
While HER2 positivity is most famously associated with breast cancer, ERBB2 amplification is a driving factor in several other malignancies. Approximately 15% to 20% of all breast cancers exhibit this amplification, making it a well-established sub-type. Testing for HER2 status is a routine part of diagnosis in this context.
The second most common site is the stomach, specifically in gastric cancer and cancers of the gastroesophageal junction. In these adenocarcinomas, HER2 overexpression is found in a subset of cases, typically ranging from 10% to 30%. Recognition of this marker in gastric tumors has led to the development of targeted therapies for this disease.
HER2 amplification has also been identified in smaller percentages of other cancer types, indicating a broader biological significance. These include:
- Colorectal cancer, where it can occur in a distinct subgroup.
- Malignancies of the bladder.
- Salivary gland cancer.
- Non-small cell lung cancer, opening new avenues for molecular testing and treatment.
Signaling Consequences: How Overexpression Fuels Cancer
The large number of HER2 receptors on the cancer cell surface creates continuous, uncontrolled activation, even without external growth factors. The density of the receptors increases the probability of them spontaneously pairing up, forming both homodimers and hyperactive heterodimers with other ErbB family members. This ligand-independent activation results in a perpetual “go” signal for cell growth and survival.
This hyperactivation initiates a cascade of intracellular signals that hijack the cell’s normal regulatory pathways. The two primary pathways continuously driven by this overexpression are the Mitogen-Activated Protein Kinase (MAPK) pathway and the Phosphatidylinositol 3-Kinase (PI3K)/Akt pathway. Both pathways regulate cell fate.
The constant signaling through the MAPK pathway drives uncontrolled cell proliferation, causing cancer cells to divide rapidly and aggressively. Simultaneously, the PI3K/Akt pathway promotes cell survival by inhibiting apoptosis, the process of programmed cell death. This prevents the cancer cell from self-destructing and contributes to increased angiogenesis, the formation of new blood vessels that feed the tumor. The combined effect of excessive growth, resistance to death, and enhanced blood supply is the aggressive phenotype characteristic of HER2-positive cancers.