The Role of ErbB Receptors in Endometrial Cancer

Endometrial cancer (EC) is the most common malignancy of the female genital tract. Overall, about 2% to 3% of women develop EC during their lifetime [Jemal et al., 2006]. EC is a malignancy that occurs primarily in postmenopausal women. Based on clinical and pathological features, EC is classified into 2 types [Bokhman, 1983]. Type I EC, represents the majority of sporadic EC cases (70-80%), is usually well differentiated and endometrioid in histology. Type II EC, represents the minority of sporadic EC cases (10-20%), is poorly differentiated and usually papillary serous or clear cell in histology [Bokhman, 1983; Lax, 2004; Doll et al., 2008]. The Epidermal Growth Factor system (EGF system) is present in human organs and play important role in embryogenesis and postnatal development [Casalini et al., 2004; Uberall et al., 2008]. Dysregulation of the EGF signaling network is implicated in various disorders [Marmor et al., 2004; Uberall et al., 2008]. In cancer, the EGF system contributes in proliferation, transformation, angiogenesis, migration and invasion [Holbro et al., 2003].


Introduction
Endometrial cancer (EC) is the most common malignancy of the female genital tract.Overall, about 2% to 3% of women develop EC during their lifetime [Jemal et al., 2006].EC is a malignancy that occurs primarily in postmenopausal women.Based on clinical and pathological features, EC is classified into 2 types [Bokhman, 1983].Type I EC, represents the majority of sporadic EC cases (70-80%), is usually well differentiated and endometrioid in histology.Type II EC, represents the minority of sporadic EC cases (10-20%), is poorly differentiated and usually papillary serous or clear cell in histology [Bokhman, 1983;Lax, 2004;Doll et al., 2008].The Epidermal Growth Factor system (EGF system) is present in human organs and play important role in embryogenesis and postnatal development [Casalini et al., 2004;Uberall et al., 2008].Dysregulation of the EGF signaling network is implicated in various disorders [Marmor et al., 2004;Uberall et al., 2008].In cancer, the EGF system contributes in proliferation, transformation, angiogenesis, migration and invasion [Holbro et al., 2003].

Receptors and ligands
The EGF system is present in human organs and play important role in cell proliferation, differentiation and apoptosis during embryogenesis and postnatal development [Casalini et al., 2004;Uberall et al., 2008].
The extracellular region of ErbB receptors has 4 subdomains (I-IV).Subdomains I and III (also called L1 and L2) are important for ligand binding.Subdomain II (also called S1) is important for dimerization between two receptors [Ogiso et al., 2002].

Src kinase pathway
The Src kinase pathway regulates cell proliferation, migration, adhesion, angiogenesis, and immune function.Src is a member of a 10 gene family (FYN, YES, BLK, FRK, FGR, HCK, LCK, LYN, SRMS) of non-RTKs.It is located in the cytoplasm and cross-connected with other signaling pathways, such as PI3K and STAT pathway [Yeatman, 2004;Summy & Gallick, 2006;].Although Src functions independently, it may interact with RTKs such as EGFR.The interaction between Src and EGFR may enhance ErbB signaling and may be involved in resistance to EGFR targeted therapy [Jorissen et al., 2003;Leu & Maa, 2003].

The role of epidermal growth factor system in carcinogenesis
Dysregulation of the EGF system signaling network is implicated in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [Marmor et al., 2004;Uberall et al., 2008].Loss of control of the cell functions mediated by the EGF system signaling network is a hallmark of oncogenesis, in which the balance between cell proliferation and differentiation is disturbed.Several types of human cancers associated with dysregulation of the EGF system signaling network [Uberall et al., 2008].

Expression and clinical significance of ErbB receptors in endometrial cancer
Due to the inactive status of postmenopausal endometrium, it is expectable to find significantly higher expression of the 4 ErbB receptors in EC tissue [Ejskjaer et al., 2007].EGFR, in endometrium, is localized to the basal part of surface epithelial cells, only in stromal cells, or both to epithelial and stromal cells [Bigsby et al., 1992;Wang et al., 1994;Imai et al., 1995;Möller et al., 2001;Ejskjaer et al., 2005].It is primarily located to the cell membrane but also to the cytoplasm [Nyholm et al., 1993;Reinartz et al., 1994;Khalifa et al., 1994;Niikura et al., 1996;Ejskjaer et al., 2007].

www.intechopen.com
In unselected patients with EC, it has been reported EGFR expression in 43-67% of cases [Reinartz et al., 1994;Khalifa et al., 1994;Scambia et al, 1994;Niikura et al., 1996;Androutsopoulos et al., 2006;Adonakis et al., 2008].In patients with type I EC, it has been reported EGFR expression in 46% of cases.In patients with type II EC, it has been reported EGFR expression in 34% of cases [Konecny et al., 2009].Although the clinical significance of EGFR has not been studied well in EC, it may have a dual role.EGFR overexpression did not affect disease progression in type I EC, although affects disease progression in type II EC.EGFR overexpression in type II EC associated with high grade and adverse clinical outcome [Konecny et al., 2009].ErbB-2, in endometrium, is localized baso-laterally in the glands and surface epithelial cells [Bigsby et al., 1992;Wang et al., 1994;Miturski et al., 1998;Ejskjaer et al., 2005].It is located to the cell membrane [Reinartz et al., 1994;Khalifa et al., 1994;Ejskjaer et al., 2007;Odicino et al., 2008].In unselected patients with EC, ErbB-2 amplification/overexpression represents a rare event.

Endometrial cancer and ErbB-targeted therapies
EGFR and ErbB-2 as targets for cancer therapy have been investigated for over 20 years.Two major classes of ErbB-targeted therapies have been developed.
The role of ErbB-targeted therapies in EC should be further investigated in clinical trials to evaluate their therapeutic efficacy [Odicino et al., 2008;Oza et al., 2008;Santin et al., 2008;Konecny et al., 2009;Fleming et al., 2010;Santin, 2010].Also, further studies into the molecular pathways of EC development and progression, will increase our knowledge of this disease and will lead to the discovery of new generation molecules with higher therapeutic efficacy.

Conclusion
Additional studies into the molecular pathways of EC development and progression, will increase our knowledge of this disease and will lead to the discovery of new generation molecules with higher therapeutic efficacy.