The EGF system is present in human organs and play important role during embryogenesis and postnatal development [3] [4] . It has 4 receptors: epidermal growth factor receptor (EGFR or ErbB-1), ErbB-2, ErbB-3 and ErbB-4 [3] [6] [7] .

ErbB receptors belong to subclass I of the superfamily of Receptor Tyrosine Kinases (RTKs) [3] [6] . They are trans-membrane glycoproteins with an extracellular region containing two ligand-binding domains, an extracellular juxtamembrane region, a hydrophobic transmembrane domain and an intracellular domain with tyrosine kinase activity [7] [8] . ErbB receptors catalyze the transfer of the γ phosphate of ATP to hydroxyl groups of tyrosines in target proteins [9] .

Moreover, EGF system has numerous ligands. According to their affinity for one or more ErbB receptors, the ligands divided into:

1) Ligands with binding specificity for EGFR: EGF, transforming growth factor-a (TGF-a) and amphiregulin (AR) [6] [7] [10] .

2) Ligands with dual binding specificity for EGFR and ErbB-4: betacellulin (BTC), heparin-binding growth factor (HB-EGF) and epiregulin (EPR) [6] [7] [10] .

3) Ligands with binding specificity for ErbB-3 and ErbB-4: neuregulins (NRGs) or heregulins (HRGs). They divided in two subgroups based on their ability to bind ErbB-3 and ErbB-4 (NRG-1 and NRG-2) or only ErbB-4 (NRG-3 and NRG-4) [6] [7] [10] -[12] .

The ligands for ErbB receptors bind to the extracellular domain, resulting in receptor activation by homodimer and/or heterodimer formation and the subsequent transphosphorylation of tyrosine residues in the cytoplasmic region [6] [7] [13] . However, there is no direct ligand for ErbB-2 receptor [6] .

The extracellular region of EGFR, ErbB-3 and ErbB-4 has two distinct conformations: the closed conformation (inactive) and the open conformation (active) [8] [14] [15] .

In the absence of ligand binding, the extracellular region of EGFR, ErbB-3 and ErbB-4 has equilibrium between closed and open conformation [8] [14] -[16] . This equilibrium favours the closed conformation [8] [16] .

Ligand binding stabilizes extracellular region in the open conformation and leads to the formation of both homodimeric and heterodimeric ErbB receptor complexes [8] [15] -[17] . The dimeric formation triggers receptor activation by an allosteric mechanism [18] . That leads to intracellular kinase activation and initiation of downstream signaling pathways [7] [17] [19] .

The extracellular region of ErbB-2 has a conformation not suitable for ligand binding [20] . However, ErbB-2 is capable for ligand independent dimerization and signaling [8] [20] . At elevated expression levels ErbB-2 homodimerizes [20] . Moreover, ErbB-2 heterodimerizes with other ErbB receptors and it is their preferred heterodimerization partner [7] [17] [20] -[22] .

ErbB-3 lacks intrinsic tyrosine kinase activity [23] . It can initiate signaling only in association with another ErbB receptor, usually ErbB-2 [23] .

The dimerization of ErbB receptors represents the fundamental mechanism that drives transformation [24] . Although both homodimerization and heterodimerization result in activation of the EGF signaling network, heterodimers are more potent and mitogenic [5] .

Dimerization of ErbB receptors leads to intracellular kinase activation [7] [17] [19] . As a result, a number of tyrosine residues in the COOH-terminal portion of ErbB receptors become phosphorylated [6] [20] [24] . These phosphorylated tyrosine residues function as docking sites for cytoplasmic proteins containing Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains [5] [7] [24] [25] . Recruitment of proteins initiates intracellular signaling via several pathways:

1) Ras/Raf/mitogen-activated protein kinase (MAPK) pathway [26] -[30] .

2) Phosphatidylinositol 3-kinase (PI3K)/Akt pathway [26] [31] -[34] .

3) Signal transducers and activators of transcription (STAT) pathway [35] -[39] .

4) Src Kinase pathway [40] -[43] .

5) Phospholipase Cγ/protein kinase C pathway [44] -[47] .

Dysregulation of the EGF signaling network is implicated in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [3] [5] .

Loss of control of the cell functions mediated by the EGF signaling network is a hallmark of oncogenesis, in which the balance between cell proliferation and differentiation is disturbed. Several types of human cancer associated with dysregulation of the EGF signaling network [3] .

In cancer, the EGF signaling network becomes hyperactivated with various mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation) [5] [7] [48] . Moreover contributes in proliferation, transformation, angiogenesis, migration and invasion [6] .

EC is the most common malignancy of the female genital tract [1] . Based on clinical and pathological features, sporadic EC is classified into 2 types [49] [50] .

1) Type I EC, represents the majority of sporadic EC cases (70% - 80%) [49] [50] . It is usually well differentiated and endometrioid in histology [49] -[51] . It is estrogen-related, usually arises from endometrial hyperplasia, has less aggressive clinical course and favorable prognosis [49] [50] [52] .

2) Type II EC, represents the minority of sporadic EC cases (10% - 20%) [49] [50] . It is poorly differentiated and usually papillary serous or clear cell in histology [49] -[51] . It is not estrogen-related, arises from atrophic endometrium, has aggressive clinical course and propensity for early spread and poor prognosis [49] [53] [54] .

Due to the inactive status of postmenopausal endometrium, it is expectable to find significantly higher expression of the ErbB receptors in EC tissue [55] .

In endometrium, EGFR localized to the basal part of surface epithelial cells, only in stromal cells, or both to epithelial and stromal cells [56] -[65] . It is primarily located to the cell membrane but also located to the cytoplasm [55] [61] -[69] .

In unselected patients with EC, it has been reported EGFR expression in 43% - 67% of cases [61] -[63] [67] -[72] . In patients with type I EC, it has been reported EGFR expression in 46% of cases [63] . In patients with type II EC, it has been reported EGFR expression in 34% - 50% of cases [63] [64] [71] .

EGFR over expression may have a dual role in EC [71] . It seems that in type I EC, EGFR overexpression did not affect disease progression [71] . However in type II endometrial cancer, EGFR overexpression associated with high grade disease and adverse clinical outcome [63] [64] [71] .

In endometrium, ErbB-2 localized baso-laterally in the glands and surface epithelial cells [56] [57] [60] -[65] [73] . It is located to the cell membrane [55] [61] -[65] [67] [68] [74] .

In unselected patients with EC, ErbB-2 amplification/overexpression represents a rare event [72] . In patients with type I EC, it has been reported ΕrbB-2 receptor overexpression in 8% of cases and ErbB-2 gene amplification in 1.4% - 3% of cases [71] [75] . Although ΕrbB-2 amplification/overexpression is more common in patients with type II EC, the exact frequency remains controversial [63] [64] [71] . However, there are racial differences regarding ErbB-2 overexpression in patients with type II EC [76] . ErbB-2 overexpression is more common in Black race patients with type II EC [65] [76] .

In patients with papillary serous EC, it has been reported ΕrbB-2 receptor overexpression in 18% - 80% of cases and ΕrbB-2 gene amplification in 17% - 47% of cases [63] [64] [71] [75] [77] -[79] . In patients with clear cell EC, it has been reported ΕrbB-2 receptor overexpression in 33% of cases and ΕrbB-2 gene amplification in 16% - 50% of cases [63] [64] [71] [75] [78] . ΕrbB-2 overexpression especially in type II EC, is an indicator of a highly aggressive disease with poor overall survival [63] [64] [74] [75] [77] [80] [81] .

In endometrium, ErbB-3 localized to surface epithelial cells [60] -[65] [82] [83] . It is located to the cytoplasm, with membrane staining in a minority of samples [55] [61] -[65] [83] .

The clinical significance of ErbB-3 has not been studied well in EC [55] [61] -[65] [83] .

In endometrium, ErbB-4 localized to epithelial and stromal cells [60] -[65] [83] [84] . It is located to the cytoplasm, with membrane staining in a minority of samples [55] [61] -[65] [83] .

The clinical significance of ErbB-4 has not been studied well in EC [55] [61] -[65] [83] .

EGFR and ErbB-2 as targets for cancer therapy have been investigated for over 30 years [85] . There are 2 major classes of ErbB targeted therapies: [85] [86] .

Recent years, molecular targeted therapies have still shown modest effect in unselected EC patients [96] . Overall response rate to these drugs is modest, unless they are associated with chemotherapy or radiotherapy [85] .

ErbB targeted therapies have not clinically tested in type II EC [71] . Perhaps they may be clinically active as adjuvant therapy in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression [64] [65] [71] [87] -[89] [97] -[104] .