Her2

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

CD340; c-erbB2; HER2/new; Human epidermal growth factor receptor 2, ERBB2, Erb-b2 receptor tyrosine kinase 2

Definition
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HER2 is the acronym for "human epidermal growth factor receptor 2" and refers to a receptor tyrosine protein kinase belonging to the family of human epidermal growth factor receptors (EGF receptors). HER2 is also known as HER/new or ErbB-2. HER2 stimulates cell proliferation via the RAS-MAP kinase pathway and simultaneously inhibits apoptosis via the mTOR signalling pathway.

General information
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Allg: The family of EGF receptors comprises four members:

  • EGF-R (ErbB-1)
  • HER2/neu (ErbB-2)
  • HER3 (ErbB-3) and
  • HER4(ErbB-4).

The gene of the same name coding for the HER2 receptor protein is an oncogene whose amplification or overexpression plays an important role in the development and progression of certain aggressive carcinomas, particularly breast cancer. In recent years, the receptor protein HER2 has become an important biomarker and an important therapeutic target (e.g. for about 30% of breast cancer patients).

Pathophysiology
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HER2 receptors are transmembrane receptor proteins that receive growth signals and transmit them to various signal transduction chains via their cytoplasmic domain, which acts as a tyrosine-specific protein kinase. Among the growth factors that activate HER2 receptors, the epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) are the most important ligands. There are also a number of other growth factors that can activate one or more members of the ErbB receptor family.

An overexpression of EGF receptors, including for HER2, indicates a transformation of a healthy cell into a tumor cell (Hossam M et al. 2016). Thus, the number of EGF receptors is significantly increased in numerous malignant tumors (up to 2 million receptors per cell). This overexpression is associated with a worse prognosis, lower survival rates and increased metastasis. This refers mainly to bronchial, breast, prostate, colon and ovarian cancer. In metastatic colorectal carcinomas, EGFR overexpression is over 80%. EGFR-expressing carcinomas are more resistant to chemotherapy.

Effect: Two transmembrane EGF receptors (e.g. ErbB-3 and HER2/neu) dimerize after one of the receptors has bound a growth factor of the EGF family. The isolated binding to one receptor does not yet trigger growth impulses. Only dimerisation with a second receptor leads to activating self-phosphorylation at the cytoplasmic receptor domain and thus to activation of the RAS-MAP kinase pathway. The dimerisation can occur between two identical or also between two different ErbB receptors. Thus homo- or heterodimers are formed. Cell proliferation is induced and apoptosis is inhibited via the signal transduction chain in which various phosphorylation reactions play a role. HER2/neu is considered the preferred dimerization partner for the other ErbB receptors. This role gains in importance due to an overexpression of the receptor in tumor cells. In addition, heterodimers are particularly stable with HER2/neu and can activate intracellular signal transduction processes in a prolonged manner.

Diagnostics
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Detection methods of HER2 DNA and receptor protein from biopsy material:

  • FISH: Fluorescence in situ hybridization (detection of HER2-DNA in the cell nucleus by fluorescence technique)
  • CISH (chromogenic in situ hybridization; detection of HER2 DNA in the cell nucleus; CISH uses a gene probe labeled with digoxigenin; the staining can be evaluated under a light microscope).
  • Serum test: detection of the HER2 receptor protein (SHED antigen).

Note(s)
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HER2 is the target of the monoclonal antibody trastuzumab, among other things. Trastuzumab is an anti-HER2/neu monoclonal antibody which has been humanised by molecular biology, i.e. the immunoglobulin originally derived from the mouse has been modified in such a way that the amino acid sequence corresponds to human IgG except for the antigen-binding domain. Trastuzumab prevents dimerisation with HER2/neu.

Literature
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  1. Burstein HJ(2005) The New England Journal of Medicine 353: 1652-1564.
  2. Coussens L et al (1085) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132-1139.
  3. Mates M et al (2015) Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline". Current Oncology 22 (Suppl 1): 114-122.
  4. Roy Vet al (2009) Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer. The Oncologist 14: 1061-1069
  5. Rusnak Dwet al. (2001) The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Research 61: 7196-7203
  6. Santin AD et al (2008) Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". International Journal of Gynaecology and Obstetrics 102: 128-131.

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Last updated on: 29.10.2020