ERBB2, also known as HER2, is a gene found within human cells. This gene provides instructions for making a protein that resides on the surface of cells. The ERBB2 protein plays an important role in regulating various cellular processes, including cell growth, division, and repair.
Understanding this gene and its corresponding protein is significant in medical contexts, especially within cancer research and treatment. Its presence and activity are studied to better comprehend cellular functions and deviations that can occur in disease states. This knowledge helps scientists and doctors explore how cells maintain their normal state and what happens when those processes go awry.
Normal Role of ERBB2
In healthy human cells, the ERBB2 gene directs the production of the HER2 protein, which acts as a receptor embedded in the cell’s outer membrane. These receptors function much like an antenna, scanning the extracellular environment for specific molecular signals. When a compatible signal molecule binds to the HER2 receptor, it triggers a cascade of events inside the cell.
This signaling cascade communicates instructions for the cell to grow, divide, and repair itself, which are all processes important to maintaining healthy tissues and organs. The activity of HER2 in normal cells is tightly controlled, ensuring that cells only proliferate or repair when necessary. This precise regulation prevents unchecked growth and maintains the body’s delicate balance.
ERBB2 in Cancer Development
When the ERBB2 gene becomes dysfunctional, it can contribute to the uncontrolled cell growth characteristic of cancer. This dysfunction often manifests as “ERBB2 amplification,” meaning cells produce too many copies of the ERBB2 gene. Alternatively, it can lead to “HER2 overexpression,” where an excessive amount of the HER2 protein is present on the cell surface. Both scenarios result in an abnormally high number of HER2 receptors.
This abundance of HER2 receptors causes the signaling pathway to become overactive, sending growth signals to the cell even in the absence of external cues. The continuous activation drives cells to grow and divide, bypassing the normal regulatory mechanisms that prevent such unchecked proliferation. This growth is a hallmark of cancerous cells, leading to tumor formation and progression.
ERBB2 overexpression is most commonly observed in certain types of cancer, influencing their biological behavior. For instance, approximately 15-20% of breast cancers exhibit HER2 overexpression. Gastric (stomach) cancers and gastroesophageal junction cancers also show HER2 overexpression in about 10-30% of cases, making it a relevant factor in these malignancies. This molecular alteration defines a specific subtype of these cancers, distinguishing them from those without HER2 involvement.
Detecting ERBB2 Status
Determining a patient’s ERBB2 status, specifically whether their cancer exhibits HER2 overexpression, is a standard step in cancer diagnosis. This testing helps classify the tumor and provides guidance for treatment decisions. The primary diagnostic methods involve assessing either the amount of HER2 protein on the cell surface or the number of ERBB2 gene copies within the tumor cells.
Immunohistochemistry (IHC) is a widely used test that measures the level of HER2 protein expression. Tissue samples from a biopsy are stained with antibodies designed to bind to the HER2 protein. A pathologist then examines the stained sample under a microscope and assigns a score ranging from 0 to 3+, with scores of 3+ indicating high HER2 protein expression and classifying the cancer as HER2-positive. Scores of 1+ or 2+ are considered equivocal and usually require further testing.
For cases with equivocal IHC results or as a direct method to assess gene amplification, Fluorescence In Situ Hybridization (FISH) or Chromogenic In Situ Hybridization (CISH) are employed. These tests detect the number of ERBB2 gene copies within the cancer cells. FISH uses fluorescent probes that bind to the ERBB2 gene, while CISH uses non-fluorescent probes. The results are typically reported as a ratio of ERBB2 gene copies to copies of a control gene, with a ratio above a certain threshold, often 2.0, indicating ERBB2 gene amplification and a HER2-positive status.
Targeted Therapies for ERBB2-Positive Cancers
For cancers identified as HER2-positive, specific treatments known as targeted therapies have been developed to interfere with the HER2 pathway. These therapies differ from traditional chemotherapy by precisely aiming at the molecular mechanisms that drive HER2-positive cancer growth, often resulting in fewer side effects on healthy cells. The development of these agents has improved outcomes for patients with these specific cancer types.
One class of HER2-targeted drugs includes monoclonal antibodies, such as trastuzumab and pertuzumab. Trastuzumab works by binding to the extracellular domain of the HER2 receptor, preventing it from sending growth signals and marking HER2-overexpressing cells for destruction by the immune system. Pertuzumab, often used in combination with trastuzumab, binds to a different part of the HER2 receptor, further blocking its ability to pair with other HER receptors and initiate signaling.
Another approach involves antibody-drug conjugates (ADCs), which combine a HER2-targeting antibody with a potent chemotherapy drug. Examples include trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan. These ADCs deliver the chemotherapy payload directly to HER2-positive cancer cells, minimizing systemic exposure to the cytotoxic agent and thereby reducing side effects while maximizing drug concentration at the tumor site. After binding to HER2, the ADC is internalized by the cancer cell, releasing the chemotherapy to kill the cell.
Tyrosine kinase inhibitors (TKIs), such as lapatinib and tucatinib, represent a third class of targeted agents. These small molecules work by entering the cell and blocking the intracellular portion of the HER2 receptor, specifically inhibiting the enzyme activity that normally transmits growth signals. By directly interfering with this internal signaling, TKIs can stop the uncontrolled proliferation driven by an overactive HER2 pathway. The introduction of these diverse therapeutic strategies offers more precise and effective options for patients.