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They are composed of an extracellular domain ECD , a transmembrane segment and an intracellular region [ 22 ]. The ECD domain is divided into four parts: domains I and III, which play a role in ligand binding, and domains II and IV, which contain several cysteine residues that are important for disulfide bond formation [ 23 ].
The transmembrane segment is composed of 19—25 amino acid residues. The intracellular region is composed of a juxtamembrane segment, a functional protein kinase domain with the exception of HER3 that lacks tyrosine kinase activity [ 24 ] and must partner with another family member to be activated [ 25 ] , and a C-terminal tail containing multiple phosphorylation sites required for propagation of downstream signaling [ 23 ].
HER receptors are activated by both homo- and heterodimerization, generally induced by ligand binding [ 27 ]. This suggests that HER receptor family has evolved to provide a high degree of signal diversity [ 28 ]. The cellular outcome produced by HER receptors activation depends on the signaling pathways that are induced, as well as their magnitude and duration, which are influenced by the composition of the dimer and the identity of the ligand [ 28 ].
Several growth factor ligands interact with the HER receptors [ 29 ]. However, no known ligand can promote HER2 homodimer formation, implying that no ligand can bind directly to HER2 [ 30 ]. The structural basis for receptor dimerization has been elucidated in recent years through crystallographic studies [ 31 , 32 ].
Dimerization is mediated by the dimerization arm, a region of the extracellular region of HER receptors. While in its inactivated state the dimerization arm of EGFR, HER3 and HER4 is hidden, ligand binding induces a receptor conformational change leading to exposure of the dimerization arm [ 31 ]. In contrast to the other three HER receptors, the dimerization arm of the HER2 receptor is permanently partially exposed, thus permitting its dimerization even if the HER2 receptor lacks ligand-binding activity [ 32 ].
Interaction between the dimerization arms of two HER receptors promotes the formation of a stable receptor dimer in which the kinase regions of both receptors are closed enough to permit transphosphorylation of tyrosine residues, i. The first member of the dimer mediates the phosphorylation of the second, and the second dimer mediates the phosphorylation of the first [ 23 ]. The phosphorylation of specific tyrosine residues following HER receptor activation and the subsequent recruitment and activation of downstream signaling proteins leads to activation of downstream signaling pathways promoting cell proliferation, survival, migration, adhesion, angiogenesis and differentiation [ 35 ].
These downstream signaling cascades control cell cycle, cell growth and survival, apoptosis, metabolism and angiogenesis [ 37 , 38 ]. Signaling from HER receptors is then terminated through the internalization of the activated receptors from the cell surface by endocytosis. HER heterodimers produce more potent signal transduction than homodimers. This can be explained by the fact that heterodimerization provides additional phosphotyrosine residues necessary for the recruitment of effector proteins [ 28 ].
Heterodimerization follows a strict hierarchical principle with HER2 representing the preferred dimerization and signaling partner for all other members of the HER family [ 41 ]. HER2 seems to function mainly as a co-receptor, increasing the affinity of ligand binding to dimerized receptor complexes [ 42 , 43 ].
HER2 has the strongest catalytic kinase activity [ 41 ] and HER2-containing heterodimers produce intracellular signals that are significantly stronger than signals generated from other HER heterodimers [ 44 ].
Furthermore, HER2 containing heterodimers have a slow rate of receptor internalization, which results in prolonged stimulation of downstream signaling pathways [ 28 ]. Whereas in normal cells the activity of tyrosine kinases is a tightly controlled mechanism, in cancer cells, alterations in tyrosine kinases—overexpression of receptor tyrosine kinase proteins, amplification or mutation in the corresponding gene, abnormal stimulation by autocrine growth factors loop or delayed degradation of activated receptor tyrosine kinase—lead to constitutive kinase activation and therefore to aberrant cellular growth and proliferation [ 34 , 47 ].
Several ways of aberrant activation of HER receptors have been described, including ligand binding, molecular structural alterations, lack of the phosphatase activity, or overexpression of the HER receptor [ 53 ].
The increased amount of cell surface HER2 receptors associated with HER2 overexpression leads to increased receptor-receptor interactions, provoking a sustained tyrosine phosphorylation of the kinase domain and therefore constant activation of the signaling pathways.
While HER1 undergoes endocytic degradation after ligand-mediated activation and homodimerization, HER1-HER2 heterodimers evade endocytic degradation in favor of the recycling pathway [ 57 , 58 ], resulting in increased HER1 membrane expression and activity [ 55 , 56 , 59 ].
It has also been reported that HER2 overexpression enhances cell proliferation through the rapid degradation of the cyclin-dependent kinase Cdk inhibitor p27 and the upregulation of factors that promote cell cycle progression, including Cdk6 and cyclins D1 and E [ 60 ]. Here below, we present some of the existing techniques that are used for the HER2 determination in clinical practice. By this method, it is possible to estimate the number of cells showing membranous staining in the tissue section as well as the intensity of the staining [ 62 ].
Membranous staining in the invasive component of specimen is scored on a semi-quantitative scale. IHC is an easy and relatively inexpensive method [ 63 ]. As mentioned before, HER2 receptor is composed of an extracellular domain ECD , a transmembrane domain, and an intracellular domain with tyrosine kinase activity. This is mainly due to the fact that studies that analyzed the association between HER2 ECD levels and prognostic and predictive factors in breast cancer patients reported conflicting results, depending on which cutoff value was considered or which assay was used [ 71 ].
ELISA is an easy and fast method. The HER2 gene locus on chromosome 17 is recognized by the HER2 probe, which is labeled with a fluorophore orange as example. Fluorescent hybridization signals can be visualized using a fluorescence microscope equipped with appropriate filters for example Spectrum Orange for locus-specific probe HER2, Spectrum Green for centromeric probe 17, and the UV filter for the DAPI nuclear counterstain [ 76 ].
In order to adequately evaluate HER2 status, a minimum of 20 tumor cell nuclei are counted in at least two invasive tumor areas. For equivocal FISH specimens, results are confirmed by counting 20 additional cells [ 61 ].
Moreover, the equivocal category requires reflex testing with the alternative assay IHC on the same specimen for final determination. If specimen is evaluated as equivocal, even after reflex testing, the oncologist may consider targeted treatment. Although still matter of debate, several researchers consider FISH as being more accurate and reliable than IHC in the assessment of HER2 status in breast cancer specimens [ 77 , 78 , 79 , 80 ]. In addition, given that DNA is more stable than protein, preanalytical factors have less impact on assay results compared with IHC [ 81 ].
Although the FISH technique yields results that are considered more objective and quantitative than immunohistochemical scoring [ 73 , 82 ], this method is nine times more time-consuming [ 83 ] and three times more expensive compared with IHC [ 84 ].
In addition, costly equipment is required for signal detection [ 67 ].
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