Molecular Mechanisms, Expression and Clinical Role of ErbB Receptors in Endometrial Cancer

Introduction

The epidermal growth factor system (EGF system) is present in various human organs [1, 2]. It has an important role in cell proliferation, differentiation and apoptosis during embryogenesis and postnatal development [1, 2].

Dysregulation of the EGF system signaling network is involved in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [1, 3].

Especially in cancer, the EGF system signaling network becomes hyperactivated with a variety of mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation) [3,4].

Furthermore, the EGF system in cancer contributes in proliferation, transformation, angiogenesis, migration and invasion [5]. Recent years the receptors of the EGF system, are potential targets in cancer treatment [6, 7].

Molecular Biology of ErbB Receptors

The EGF system has 4 receptors (EGFR, ErbB-2, ErbB-3 and ErbB-4) and numerous ligands [1,4, 5].

ErbB receptors are trans-membrane glycoproteins and belong to the superfamily of Receptor Tyrosine Kinases (RTKs) [1, 5]. They have an extracellular region with two ligand-binding domains, an extracellular juxtamembrane region, a hydrophobic transmembrane domain and an intracellular domain with tyrosine kinase activity [4, 8]. They catalyze the transfer of the γ phosphate of ATP to the hydroxyl groups of tyrosines in target proteins [9].

The extracellular region of EGFR, ErbB-3 and ErbB-4 has 2 distinct conformations. The closed conformation of extracellular region is inactive. The open conformation of extracellular region, is active and permits interactions with a ligand . In the absence of ligand binding, there is an equilibrium between the 2 conformations that favors the closed conformation [8, 10-12].

Ligand binding stabilizes the extracellular region in the open conformation, leads to the formation of homodimeric and heterodimeric ErbB receptor complexes and activates ErbB receptors by an allosteric mechanism [8, 11-14]. That leads to intracellular kinase activation and initiation of downstream signaling pathways [4, 13, 15]. However, ErbB-3 has no intrinsic tyrosine kinase activity and initiates signaling only in association with another ErbB receptor, usually ErbB-2 [16].

The extracellular region of ErbB-2 has a conformation not suitable for ligand binding [17]. However, ErbB-2 is capable for ligand independent dimerization and signaling [8, 17]. ErbB-2 heterodimerizes with other ErbB receptors and is their preferred heterodimerization partner [4, 13, 17]. Moreover, at elevated expression levels ErbB-2 homodimerizes [17].

Signaling Pathways of ErbB Receptors

Dimerization of ErbB receptors leads to intracellular kinase activation [4, 13, 15]. Subsequently, a number of tyrosine residues in the COOH-terminal portion of ErbB receptors becomes phosphorylated [5, 17, 18]. That phosphorylated tyrosine residues function as docking sites for cytoplasmic proteins containing Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains [3, 4, 18]. Recruitment of protein initiates intracellular signaling via several pathways:

1. Ras/Raf/mitogen-activated protein kinase (MAPK) pathway (regulates cell proliferation and survival) [Figure 1] [19, 20].
2. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway (regulates cell growth, apoptosis, tumor invasion, migration and resistance to chemotherapy) [Figure 1] [21, 22].
3. Signal transducers and activators of transcription (STAT) pathway (regulates oncogenesis and tumor progression) [Figure 1] [23].
4. Src Kinase pathway (regulates cell proliferation, migration, adhesion, angiogenesis and immune function) [Figure 1] [24,25].
5. Phospholipase Cγ/protein kinase C pathway [Figure 1] [26, 27].

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Figure 1. Signaling pathways of ErbB receptors [4, 13, 15, 19-27].

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Expression of ErbB receptors in EC

Due to the inactive status of postmenopausal endometrium, we expect to find significantly higher expression of the 4 ErbB receptors in EC tissue [28].

EGFR localized to the basal part of surface epithelial cells, only in stromal cells, or both, of epithelial and stromal cells of endometrium [29-36]. It is primarily located in the cell membrane but also located in the cytoplasm [28, 32-40].

In unselected EC patients, there is EGFR expression in 43-67% of cases [32-34, 36, 38-43]. In patients with Type I EC, there is EGFR expression in 46% of cases [34]. In patients with Type II EC, there is EGFR expression in 34-50% of cases [34, 35, 42, 44, 45].

ErbB-2 localized base-laterally in the glands and surface epithelial cells of endometrium [6, 29, 46]. It is located to the cell membrane [8, 28, 32-36, 39, 47].

In unselected EC patients, ErbB-2 amplification/overexpression represents a rare event [43]. In patients with Type I EC, there is ΕrbB-2 receptor overexpression in 8% of cases and Erb-2 gene amplification in 1.4-3% of cases [42, 48]. Although ΕrbB-2 amplification/ overexpression is ore common in patients with type II EC, the exact frequency remains controversial [34, 35, 42]. Moreover, there are racial differences regarding ErbB-2 overexpression in patients with type II EC [49]. ErbB-2 overexpression is more common in Black race patients with type II EC [49].

In patients with papillary serous EC, there is ΕrbB-2 receptor overexpression in 18%-80% of cases and ΕrbB-2 gene amplification in 17-47% of cases [34,35, 42, 48, 50-52]. In patients with clear cell EC, there is ΕrbB-2 receptor overexpression in 33% of cases and ΕrbB-2 gene amplification in 16-50% of cases [34, 35, 42, 48, 51].

ErbB-3 localized to surface epithelial cells of endometrium [31,-36, 53, 54]. It is located in the cytoplasm, with membrane staining in a minority of samples [28, 32-36, 54].

ErbB-4 localized to epithelial and stromal cells of endometrium [31-36, 54, 55]. It is located in the cytoplasm, with membrane staining in a minority of samples [28, 32-36, 54].

Clinical role of ErbB receptors in EC

Recent years, the clinical role of ErbB receptors (especially EGFR and ΕrbB-2) in EC patients, have increasing popularity [35, 36, 42, 44, 45, 56-58].

EGFR may have a dual role in EC [42]. EGFR overexpression did not affect disease progression in patients with type I EC, although affects disease progression in Type II EC [42]. More specifically EGFR overexpression in patients with Type II EC, associated with high grade disease and adverse clinical outcome [34, 35, 42, 44, 45].

Moreover, ΕrbB-2 overexpression especially in patients with Type II EC, is an indicator of a highly aggressive disease with poor overall survival [34, 35, 44, 45, 47, 48, 50, 59, 60].

ErbB-3 overexpression in patients with EC, has an unclear clinical role and not well studied [28, 32, 35, 44, 45, 54, 61]. The clinical role of ErbB-4 in patients with EC, is poorly understood and not well studied [28, 32-35, 44, 45,54, 62]. It is obvious that ErbB receptors (especially EGFR and ΕrbB-2) in EC patients, are potential targets of molecular targeted therapies [35, 36, 42, 44, 45, 56, 58, 63]. Anti-ErbB MoAbs (cetuximab, panitumumab, trastuzumab, pertuzumab) may be an attractive treatment option, especially in EC patients with advanced, recurrent or metastatic disease and overexpression of EGFR and ErbB-2 [6, 7, 34-36, 44, 56, 64, 65].

However, a phase II study (NCT00392769) failed to demonstrate significant activity of cetuximab in unselected EC patients with advanced or recurrent disease [66, 67]. The clinical efficacy of trastuzumab in EC, has been reported in several case reports [64, 68-70]. However, a phase II study of Gynecologic Oncology Group (GOG-181B) failed to demonstrate significant activity of trastuzumab in unselected EC patients with advanced or recurrent disease and overexpression of ErbB-2 [71]. Moreover, an ongoing randomized phase II study (NCT01367002) evaluates the efficacy of carboplatin/paclitaxel with or without trastuzumab in selected EC patients (papillary serous) with advanced or recurrent disease and overexpression of ErbB-2 [72].

ErbB-specific TKIs (gefitinib, erlotinib, lapatinib, afatinib) may be another attractive treatment option in EC patients with advanced, recurrent or metastatic disease and overexpression of EGFR and ErbB-2 [34-36, 44, 45, 56, 73-75]. However, a phase II study of the Gynecologic Oncology Group (GOG-229C) failed to demonstrate significant activity of gefitinib in unselected EC patients with persistent or recurrent disease [75]. Also, a phase II study (NCIC IND-148) failed to demonstrate significant activity of erlotinib in unselected EC patients with advanced or metastatic disease [74].

Moreover, a phase II study of the Gynecologic Oncology Group (GOG-229D) failed to demonstrate significant activity of lapatinib in unselected EC patients with persistent or recurrent disease [73]. It is obvious that ErbB-targeted therapies have only modest effect in unselected EC patients [34, 35, 44, 45, 56, 58, 63, 76]. Further studies into the molecular pathways of EC, may increase our knowledge regarding ErbB receptors and ErbB-targeted therapies [34, 44]. Perhaps the clinical role of ErbB receptors is more important in type II EC patients [34, 35, 44, 45, 47, 48, 50, 59, 60]. Also, ErbB-targeted therapies may be more effective as adjuvant treatment in type II EC patients with EGFR and ErbB-2 over expression [35, 36, 42, 44, 56-58, 64, 68, 69, 71-81].

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