The term HER2-positive describes a specific biological characteristic found in certain cancers, most notably a subset of breast and gastric tumors. This status indicates that cancer cells are making too much of a particular protein, which results in a more aggressive disease course and guides specific therapeutic decisions. Understanding what causes a cancer to be HER2-positive requires examining the normal function of this protein and the precise genetic change that forces its overproduction.
The Role of HER2 in Normal Cell Function
The HER2 protein is a type of receptor found on the surface of healthy human cells, acting like a cellular antenna to receive external signals. It belongs to a group of four related molecules known as the Epidermal Growth Factor Receptor (EGFR) family. These receptors are responsible for regulating fundamental processes such as cell division, repair, and survival throughout the body.
In a healthy cell, HER2 exists in a ready-to-activate state, but it is unique among its family members because it does not bind directly to any known growth factor signal. Instead, it serves as the preferred partner for the other three EGFR family members—HER1, HER3, and HER4—after they have bound their specific growth factors. When a growth factor connects to a partner receptor, that partner physically links up with HER2 in a process called heterodimerization. This pairing forms a highly active signal complex that transmits instructions for controlled growth and survival into the cell’s interior. Because the normal cell surface only has a small number of HER2 receptors, the resulting growth signals are kept at a low, regulated level necessary for normal tissue maintenance.
The Genetic Error Underlying HER2 Positive Status
The HER2-positive status in cancer is rooted in a specific genetic anomaly affecting the instruction manual for the HER2 protein. This instruction manual is a gene called ERBB2, which resides on chromosome 17 in the cell’s nucleus. In a healthy cell, there are typically two copies of the ERBB2 gene, which is the normal genetic dose for any human gene.
The fundamental error that defines a HER2-positive cancer is known as gene amplification. This process involves the cancer cell acquiring an abnormally high number of copies of the ERBB2 gene. Instead of the normal two copies, a tumor cell may possess anywhere from 10 to over 50 copies of the gene. This massive increase in the genetic blueprint acts like repeatedly hitting the “print” button on a copier.
The consequence of having too many gene copies is a phenomenon called protein overexpression. Each extra copy of the ERBB2 gene directs the cell’s machinery to produce more HER2 protein. This results in a drastically elevated number of HER2 receptors displayed on the cell surface, sometimes reaching up to 2 million receptors per cell, compared to the few thousand normally present. Specialized testing, such as Fluorescence In Situ Hybridization (FISH) or Immunohistochemistry (IHC), is used to count the number of ERBB2 gene copies or the amount of HER2 protein, respectively, to determine if a cancer is classified as positive.
How Overexpressed HER2 Drives Cancer Growth
The excessive number of HER2 receptors on the cancer cell surface fundamentally changes the receptor’s behavior, transforming it into an unregulated driver of growth. When the HER2 protein is overexpressed, the receptors become so densely packed that they spontaneously pair up with each other, a process known as homodimerization. This close proximity allows the receptors to activate their internal signaling components without needing an external growth factor to initiate the process.
The overexpressed HER2 also becomes highly efficient at forming potent pairs with its family members, particularly HER3, leading to powerful heterodimers. The HER2/HER3 pair is considered the most powerful signaling complex in the EGFR family, acting as a hyperactive switch for cell division. These constant homodimer and heterodimer formations trigger a powerful signal cascade inside the cell.
This constant “ON” signal bypasses the cell’s normal checks and balances, relentlessly pushing the cell to divide and grow. The internal signaling pathways, such as the MAPK and PI3K/AKT pathways, are continuously activated, promoting cell proliferation, survival, and resistance to programmed cell death. This uninterrupted signaling accounts for the aggressive nature often associated with HER2-positive tumors.
The Acquisition of the Genetic Error
The genetic error that causes the ERBB2 gene amplification and subsequent HER2-positive status is an acquired change, occurring during a person’s lifetime. This type of genetic change is known as a somatic mutation, meaning it is confined to the tumor cells and is not present in the germline, or reproductive cells, of the patient. Therefore, a person with a HER2-positive tumor is not at an increased risk of passing this characteristic on to their children.
The exact cause for the amplification event itself is attributed to random errors that occur during the complex process of cell division. As cells divide and replicate their DNA, mistakes in the copying process can sometimes lead to an accidental duplication of large segments of a chromosome. In this case, the segment of chromosome 17 that contains the ERBB2 gene is copied multiple times.
These errors are not linked to a specific environmental exposure or inherited risk factor. While some inherited conditions, like mutations in the BRCA genes, predispose individuals to cancer, the ERBB2 gene amplification is a chance event that occurs in the developing tumor. The amplification often includes not only the ERBB2 gene but also neighboring genes, such as GRB7, which contribute to the tumor’s growth advantage.