Sponsored Links
-->

Tuesday, June 26, 2018

Potential Clinical Utility of Serum HER-2/neu Oncoprotein ...
src: d9aqs07uebq07.cloudfront.net

Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.


Video HER2/neu



Name

HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.


Maps HER2/neu



Gene

ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).


XL ERBB2 (HER2/NEU) amp - Amplification Probe | MetaSystems Probes
src: metasystems-probes.com


Function

The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.

Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signal transduction

Signaling pathways activated by HER2 include:

  • mitogen-activated protein kinase (MAPK)
  • phosphoinositide 3-kinase (PI3K/Akt)
  • phospholipase C ?
  • protein kinase C (PKC)
  • Signal transducer and activator of transcription (STAT)

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.


Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance ...
src: www.jimmunol.org


HER2 and cancer

Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers. It is strongly associated with increased disease recurrence and a poor prognosis. Over-expression is also known to occur in ovarian, stomach, adenocarcinoma of the lung and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma, e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer and in 30% of salivary duct carcinomas.

HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.

HER2 variations/mutations

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.

HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.


APP_Breast_1.jpg
src: bioview.com


Drugs targeting HER2

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation. Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.

Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.

It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.

Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.

The expression of HER2 is regulated by signaling through eostrogen receptors. Normally, estradiol and tamoxifen acting through the eostrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.


Phosphorylation/Cytoplasmic Localization of p21Cip1/WAF1 Is ...
src: clincancerres.aacrjournals.org


HER2 testing

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity. For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.

HER2 testing on tumour

Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.

HER2 testing on serum

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy. However, its ability to determine eligibility for trastuzumab therapy is less clear.


Breast Cancer Expressing the Activated HER2/neu Is Sensitive to ...
src: cancerres.aacrjournals.org


HER2 interactions

HER2/neu has been shown to interact with:


Figure 7. | Mitochondrial MKP1 Is a Target for Therapy-Resistant ...
src: cancerres.aacrjournals.org


See also

  • Ann Marie Rogers, campaigned for UK NHS to provide Herceptin
  • SkBr3 Cell Line, over-expresses HER2

Breast Cancer Expressing the Activated HER2/neu Is Sensitive to ...
src: cancerres.aacrjournals.org


References


A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells ...
src: clincancerres.aacrjournals.org


Further reading


Figure 7. | Mitochondrial MKP1 Is a Target for Therapy-Resistant ...
src: cancerres.aacrjournals.org


External links

  • ERBB2 expression across human cancerous and healthy tissues
  • AACR Cancer Concepts Factsheet on HER2
  • Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
  • HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
  • Receptor, erbB-2 at the US National Library of Medicine Medical Subject Headings (MeSH)

Source of article : Wikipedia