HER2 dysregulation
The HER2 receptor
This space-filling model depicts the extracellular portion of the HER2 receptor. In contrast to other HER family receptors, there are no known ligands that bind to HER2, and it exists in an open conformation at all times.2 Reproduced with permission from Lippincott Williams & Wilkins. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
HER2 overexpression and amplification
Dysregulation of HER2 signaling in cancer involves an excess of signals that stimulate cancer cells to grow and spread. It is this excess of signals, rather than a mutation in the receptor itself, that results in the deleterious effects of HER2 in cancer.1
- Gene amplification means that a cell contains too many copies of HER2, the gene that codes for the HER2 receptor3
- Receptor overexpression means that a cell contains an overabundance of HER2 receptors on the cell surface3
HER2 is the preferred dimerization partner in cancer
Although all 4 HER family receptors are capable of dimerizing with each other, HER2 is the preferred dimerization partner.2
- Unlike other HER family receptors, there are no known ligands that bind to HER22
- HER2 exists in an open conformation and is continually available to bind with other HER family receptors2
- HER2-containing dimers have increased signaling potency relative to dimers that do not contain HER23
- This is because HER2 is able to decrease the rate of ligand dissociation from its dimerized partner
HER2 dimers and their downstream signaling effects
Of the HER family members, HER2 is the preferred dimerization partner. This image is a simplified representation of the signaling pathways initiated by each of the 4 possible dimers containing HER2.2,3 Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys; Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
HER2/HER3 dimers
The HER2/HER3 dimer is of particular importance in the development of cancer:
- HER2, when dimerized with HER3, is an activator of the PI3K signaling pathway3
- PI3K may lead to a more invasive cellular phenotype
- HER2/HER3 dimers may enable cancer cells to compensate for the inhibition of other HER signaling pathways4
- In breast and ovarian cancer, the ligand heregulin, which binds only to HER3 and HER4, stimulates tumor growth through HER2/HER3 heterodimers5
- Heregulin stimulation of the HER2/HER3 heterodimer leads to increased DNA synthesis, cell cycle progression, and cell proliferation
HER1/HER2 dimers
The dimer formed by HER2 and HER1/EGFR is also of importance, particularly in ovarian cancer.6
- HER1/HER2 is the most commonly formed dimer in response to stimulation with epidermal growth factor (EGF)
- Activation of the HER1/HER2 dimer leads to initiation of the mitogen-activated protein kinase (MAPK) pathway, which leads to cell proliferation