HER-2 also known as
proto-oncogene Neu,
receptor tyrosine-protein kinase erbB-2,
CD340 (
cluster of differentiationThe cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
340) or
p185 is an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the
ERBB2 geneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Over expression of this gene is correlated with higher aggressiveness in
breast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
s. It is a member of the
ErbBThe ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
protein family, more commonly known as the epidermal growth factor receptor family.
Function
HER2 is a cell membrane surface-bound
receptor tyrosine kinaseReceptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
and is normally involved in the
signal transductionSignal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways leading to cell growth and differentiation. It is encoded within the genome by HER2/neu, a known proto-oncogene. HER2 is thought to be an
orphan receptorAn orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".-Examples:Examples of orphan...
, with none of the
EGFEpidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
family of ligands able to activate it. However,
ErbBThe ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
receptors
dimeriseIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
on ligand binding, and HER2 is the preferential dimerisation partner of other members of the ErbB family. The
HER2 gene is a proto-oncogene located at the long arm of human chromosome 17(17q21-q22).
HER2 and cancer
Approximately 30% of breast cancers have an amplification of the
HER2/neu gene or overexpression of its protein product. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis. Because of its prognostic role as well as its ability to predict response to
trastuzumabTrastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
(Herceptin US brand name) (see below), breast tumors are routinely checked for overexpression of HER2/neu. Overexpression also occurs in other cancer such as
ovarian cancerOvarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
,
stomach cancerGastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
, and biologically aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.
The
oncogeneAn oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
neu is so-named because it was derived from a rodent glioblastoma cell line, which is a type of neural tumor, hence 'neu.' HER2 is named because it has a similar structure to human
epidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
, or HER1. ErbB2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that
neu, HER2, and ErbB2 are the same.
HER2 is co-localized, and, thus, most of the time, co-amplified with the gene
GRB7Growth factor receptor-bound protein 7, also known as GRB7, is a protein which in humans is encoded by the GRB7 gene.- Function :The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules...
, which is also a proto-oncogene (active in, e.g., breast cancer, testicular germ cell tumor, gastric cancer, and esophageal cancer).
It is revealed that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.
HER2 is known to form clusters that might play a role in tumorigenesis.
Drugs targeting HER2
In clinical usage, HER2/neu is important as the target of the monoclonal
antibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
trastuzumabTrastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
(marketed as Herceptin). Trastuzumab is effective only in cancers where the HER2/neu receptor is overexpressed. One of the mechanisms of how trastuzumab works after it binds to HER2 is by increasing
p27Cyclin-dependent kinase inhibitor 1B is an enzyme that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4...
, a protein that halts cell proliferation.
Overexpression of the HER2 gene can be suppressed by the amplification of other genes and the use of the drug Herceptin. Research is currently being conducted to discover which disregulated genes may have this desired effect. Another monoclonal antibody,
PertuzumabPertuzumab is a monoclonal antibody. The first of its class in a line of agents called "HER dimerization inhibitors". By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth...
http://www.healthvalue.net/EGFR-engl.html, which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.
The expression of HER2/ERBB2 protein is regulated by
estrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
s. Furthermore,
estradiolEstradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and
tamoxifenTamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
acting through the estrogen receptor normally down-regulates the expression of HER2/ERBB2. However, when the ratio of the
coactivatorA coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
AIB-3The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' , steroid receptor coactivator-3 , or thyroid hormone receptor activator molecule 1 .-Function:NCOA3 is a transcriptional...
exceeds that of the
corepressorIn molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
PAX2Paired box gene 2, also known as PAX2 is a protein which in humans is encoded by the PAX2 gene.-Function:PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding...
, the expression of HER2/ERBB2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant
breast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Recent evidence has implicated signalling via HER2/neu in resistance to the
EGFRThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
-targeted cancer drug
cetuximabCetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
.
Interactions
HER2/neu has been shown to
interactProtein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
Beta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
,
Glycoprotein 130Glycoprotein 130 is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family...
,
PLCG1Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
,
ErbinErbb2 interacting protein also known as Erbin is a protein which in humans is encoded by the ERBB2IP gene. Discovered in 1997, Erbin is a 200kDa protein containing a PDZ domain.- Function :...
,
MUC1Mucin 1, cell surface associated or polymorphic epithelial mucin is a mucin encoded by the MUC1 gene in humans. MUC1 is a proteoglycan with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and...
,
Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, Heat shock protein 90kDa alpha (cytosolic), member A1,
DLG4PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene....
,
PIK3R2Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the PIK3R2 gene.-Interactions:PIK3R2 has been shown to interact with FYN, HER2/neu, Epidermal growth factor, Cbl gene, PIK3CD, CRKL and Macrophage colony-stimulating factor.-Further reading:...
,
PICK1PRKCA-binding protein is a protein that in humans is encoded by the PICK1 gene.-Interactions:PICK1 has been shown to interact with HER2/neu, ACCN2, Metabotropic glutamate receptor 7, BNC1, Metabotropic glutamate receptor 3, GRIA4, Dopamine transporter, GRIK1, GRIK2, GRIK3, GRIA2 and GRIA3.-Further...
and
SHC1SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
.
External links