The HER2 gene plays a significant role in regulating cell growth and division. While a normal component of cellular function, its malfunction can contribute to the development and progression of certain cancers. Understanding HER2 is important because its activity influences the behavior of cancer cells.
The HER2 Gene’s Normal Role
The HER2 gene, also known as ERBB2, provides instructions for making the human epidermal growth factor receptor 2 protein. This protein is a receptor found on the surface of various cells throughout the body, including breast cells. It belongs to a family of proteins called epidermal growth factor receptors (EGFRs), which transmit signals from outside the cell to its interior.
When activated, HER2 forms pairs with other HER family receptors, initiating signaling pathways inside the cell. These pathways act like an “on-off switch,” controlling cellular processes such as growth, division, and repair. This signaling ensures that cells grow and divide appropriately, maintaining healthy tissue function. Unlike its family members, HER2 does not directly bind to a specific signaling molecule for activation, but rather becomes active through interactions with other HER family members.
When HER2 Goes Awry
Problems arise when the HER2 gene malfunctions, leading to an excess of HER2 proteins on the cell surface. This malfunction often involves “HER2 gene amplification,” where cells have too many copies of the HER2 gene. This amplification causes “HER2 protein overexpression,” meaning there are an abnormally high number of HER2 receptors on the cell surface.
When the “on-off switch” of HER2 signaling becomes stuck in the “on” position due to this overexpression, cells receive continuous growth signals. This constant signaling leads to uncontrolled cell growth and division, a hallmark of cancer development. The abnormal activity of HER2 contributes to the unchecked proliferation of cells, fueling tumor formation and progression.
HER2’s Influence on Cancer
HER2 overexpression impacts the behavior of cancer, making it a more aggressive form of the disease. Cancers with elevated HER2 levels tend to grow and spread more rapidly than those without, and they may also have a higher chance of returning after treatment. This increased aggressiveness is due to the constant growth signals that drive rapid cell division.
While HER2 is most commonly associated with breast cancer, it is also found in other cancer types, including gastric and gastroesophageal junction cancers. It can also appear in ovarian, bladder, and lung cancers. Identifying a patient’s HER2 status is important because it directly influences the prognosis and guides the selection of treatment strategies.
How HER2 Status is Determined
Determining a patient’s HER2 status involves testing tissue samples obtained from a biopsy or surgery. Two laboratory methods are used for this assessment: Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH). IHC measures the amount of HER2 protein on the surface of cancer cells by using antibodies that bind to the protein and produce a colored stain.
IHC results are reported on a scale from 0 to 3+. A score of 0 or 1+ indicates HER2-negative status, meaning low or no HER2 protein overexpression. A score of 3+ signifies HER2-positive status, indicating significant overexpression. If the IHC result is 2+, equivocal or borderline, a FISH test is performed to confirm the HER2 status. FISH directly counts the number of HER2 gene copies within the cancer cells, using fluorescent probes that attach to the gene. A positive FISH result indicates gene amplification and confirms HER2-positive status, while a negative result confirms HER2-negative status.
Targeting HER2 in Treatment
Understanding HER2 status has advanced cancer treatment by enabling the development of targeted therapies. These “HER2-targeted therapies” are designed to block the HER2 protein, interfering with its ability to send growth signals to cancer cells. Examples include monoclonal antibodies like trastuzumab and pertuzumab, and antibody-drug conjugates such as trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan-nxki.
Trastuzumab works by binding to the HER2 receptor, slowing cell replication and flagging cancer cells for destruction by the body’s immune system. Pertuzumab binds to a different region of HER2, preventing it from pairing with other HER receptors, such as HER3, which activates growth pathways. These targeted drugs are effective because they specifically address the abnormal HER2 pathway, often leading to improved outcomes for patients with HER2-positive cancers.