HER2/neu

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

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

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 is_associated_with::glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the is_associated_with::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.

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

Function
The ErbB family is composed of four plasma membrane-bound is_associated_with::receptor tyrosine kinases, the other members being is_associated_with::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. 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 is_associated_with::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:
 * is_associated_with::mitogen-activated protein kinase (MAPK)
 * is_associated_with::phosphoinositide 3-kinase (PI3K/Akt)
 * is_associated_with::phospholipase C γ
 * is_associated_with::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 is_associated_with::apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

HER2 and cancer
Amplification or 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, and aggressive forms of uterine cancer, such as uterine serous is_associated_with::endometrial carcinoma.

HER2 is co-localized, and, most of the time, co-amplified with the gene is_associated_with::GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours.

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

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 tumors and some of these tumors 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 dimerization of this protein in the absence of a ligand.

Drugs targeting HER2
HER2 is the target of the monoclonal antibody is_associated_with::trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation. Another monoclonal antibody, is_associated_with::Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

Additionally, is_associated_with::NeuVax (is_associated_with::Galena Biopharma) is a peptide-based immunotherapy that directs "killer" is_associated_with::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+ (is_associated_with::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 estrogen receptors. Normally, is_associated_with::estradiol and is_associated_with::tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor is_associated_with::PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant is_associated_with::breast cancer.

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



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

HER2 testing on tumor
Tests are usually performed on is_associated_with::biopsy samples obtained by either is_associated_with::fine-needle aspiration, core needle biopsy, is_associated_with::vacuum-assisted breast biopsy, or surgical excision. is_associated_with::Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, is_associated_with::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 (is_associated_with::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 trastazumab therapy. However, its ability to determine eligibility for trastazumab therapy is less clear.

HER2 interactions
HER2/neu has been shown to interact with:


 * CTNNB1,
 * is_associated_with::DLG4,
 * Erbin,
 * is_associated_with::GRB2,
 * HSP90AA1,
 * IL6ST,
 * is_associated_with::MUC1,
 * is_associated_with::PICK1 and
 * is_associated_with::PIK3R2,
 * is_associated_with::PLCG1,  and
 * is_associated_with::SHC1.