The ERBB2 gene, also known as HER2 in humans, provides instructions for making a protein involved in cell growth and communication. This protein is a receptor found on the surface of cells throughout the body. Its proper function is significant for various biological processes.
The Role of ERBB2 in Healthy Cells
The ERBB2 gene codes for the human epidermal growth factor receptor 2 (HER2) protein, a receptor tyrosine-protein kinase. This protein is part of a larger family of four receptors, called the epidermal growth factor receptor (EGFR) family. In healthy cells, HER2 is located on the cell surface and helps regulate cell growth, division, and repair.
Unlike other members of the EGFR family, HER2 does not have a known ligand that binds directly for activation. Instead, HER2 is unique because its extracellular domain is always in an “open” conformation, ready for activation. This structural feature makes HER2 a preferred partner for forming pairs, or heterodimers, with other EGFR family receptors like HER1 (EGFR) or HER3.
When HER2 forms these partnerships with other activated receptors, it enhances the signaling potency of the dimerized receptors. These activated pathways then send messages inside the cell, influencing processes such as proliferation, differentiation, motility, and survival.
ERBB2 Overexpression and Cancer
When the ERBB2 gene is amplified or overexpressed, meaning there are too many copies of the gene or too much of the HER2 protein is produced, it can disrupt normal cell control mechanisms. This overexpression leads to uncontrolled cell growth and division, a characteristic feature of cancer. This amplification or overexpression often gives rise to aggressive tumor cells.
ERBB2 overexpression is associated with certain types of cancer. It is found in approximately 15% to 20% of all breast cancers, a subtype known as HER2-positive breast cancer. These cancers tend to grow and spread more rapidly than HER2-negative breast cancers. Beyond breast cancer, ERBB2 overexpression has also been observed in other cancers, including ovarian, stomach, bladder, salivary, and lung carcinomas.
In gastric and gastroesophageal junction adenocarcinomas, ERBB2 overexpression is seen in about 20% to 23% of cases. This overexpression is also linked to a less favorable outlook in gastric cancer patients.
Identifying and Treating ERBB2-Positive Cancers
Identifying ERBB2-positive cancers is important for treatment planning. Two common methods used are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC tests measure the amount of HER2 protein on the surface of cancer cells, with results typically scored from 0 to 3+. A score of 0 or 1+ usually indicates HER2-negative, while 3+ is considered HER2-positive.
If the IHC result is 2+, it is considered equivocal, and further testing with FISH is often recommended to confirm the HER2 status. FISH tests examine the number of copies of the HER2 gene inside the cancer cell nucleus. These tests are performed on tissue samples obtained from biopsies or surgical removal of the tumor. The precise identification of HER2 status helps guide the selection of appropriate therapies.
Targeted therapies have been developed to specifically counteract the effects of ERBB2 overexpression. Trastuzumab (Herceptin) is an antibody that binds to the extracellular domain of the HER2 receptor, blocking HER2 from signaling the cell to grow and divide, and signaling the immune system to destroy cancer cells. Another antibody, pertuzumab, binds to a different part of HER2, preventing its interaction with other receptors and disrupting signaling.
Other HER2-targeted treatments include antibody-drug conjugates like trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). These combine an antibody with a chemotherapy drug, allowing for targeted delivery of the chemotherapy directly to HER2-positive cancer cells. Additionally, tyrosine kinase inhibitors such as lapatinib and tucatinib are small molecules that can enter the cell and block HER2 from sending growth signals to the nucleus. These therapies have significantly improved outcomes for patients with HER2-positive cancers.