**2.3.3 Signal transducers and activators of transcription (STAT) pathway**

Signal transducers and activators of transcription (STAT) pathway regulates oncogenesis and tumor progression [Bromberg, 2002].

STAT proteins interact with phosphotyrosine residues via their Src homology domain 2 (SH2) and, on dimerization, translocate to the nucleus and induce the expression of specific target genes [Haura et al., 2005; Yu et al., 2004; Zhong et al., 1994]. Constitutive activation of STAT proteins (especially STAT-3 and STAT-5) is present in various primary cancers [Bromberg, 2002; Haura et al., 2005].

EGFR regulate STAT pathway through a Janus kinase (JAK) or a JAK independent mechanism [Kloth et al., 2003; Andl et al., 2004]. Augmented activity of EGFR and ErbB-2, promote persistent STAT-3 activation and subsequently induce oncogenesis and tumor progression [Bromberg, 2002].

#### **2.3.4 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].

#### **2.3.5 Phospholipase Cγ / protein kinase C pathway**

Phospholipase Cγ (PLCγ) interacts directly with activated EGFR and ErbB-2 and hydrolyses phosphatidylinositol 4, 5 diphosphate to inositol 1, 3, 5 triphosphate (IP3) and 1, 2 diacylglycerol (DAG) [Chattopadhyay et al., 1999; Patterson et al., 2005].

IP3 is important for intracellular calcium release. DAG is cofactor in protein kinase C (PKC) activation. Activated PKC activates MAPK and c-Jun NH2-terminal kinase [Schönwasser et al., 1998; McClellan et al., 1999].

#### **3. ErbB receptors and cancer**

#### **3.1 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].

ErbB receptor specific docking sites for p85 subunit are present on ErbB-3 and absent on EGFR [Carpenter et al., 1993; Yarden & Sliwkowski, 2001b]. EGFR dependent PI3K activation occurs through dimerization of EGFR with ErbB-3 or through the docking protein

Signal transducers and activators of transcription (STAT) pathway regulates oncogenesis

STAT proteins interact with phosphotyrosine residues via their Src homology domain 2 (SH2) and, on dimerization, translocate to the nucleus and induce the expression of specific target genes [Haura et al., 2005; Yu et al., 2004; Zhong et al., 1994]. Constitutive activation of STAT proteins (especially STAT-3 and STAT-5) is present in various primary cancers

EGFR regulate STAT pathway through a Janus kinase (JAK) or a JAK independent mechanism [Kloth et al., 2003; Andl et al., 2004]. Augmented activity of EGFR and ErbB-2, promote persistent STAT-3 activation and subsequently induce oncogenesis and tumor

The Src kinase pathway regulates cell proliferation, migration, adhesion, angiogenesis, and

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,

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

Phospholipase Cγ (PLCγ) interacts directly with activated EGFR and ErbB-2 and hydrolyses phosphatidylinositol 4, 5 diphosphate to inositol 1, 3, 5 triphosphate (IP3) and 1, 2

IP3 is important for intracellular calcium release. DAG is cofactor in protein kinase C (PKC) activation. Activated PKC activates MAPK and c-Jun NH2-terminal kinase [Schönwasser et

Dysregulation of the EGF system signaling network is implicated in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [Marmor et al.,

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

such as PI3K and STAT pathway [Yeatman, 2004; Summy & Gallick, 2006;].

resistance to EGFR targeted therapy [Jorissen et al., 2003; Leu & Maa, 2003].

diacylglycerol (DAG) [Chattopadhyay et al., 1999; Patterson et al., 2005].

**3.1 The role of epidermal growth factor system in carcinogenesis** 

**2.3.5 Phospholipase Cγ / protein kinase C pathway** 

**2.3.3 Signal transducers and activators of transcription (STAT) pathway** 

Gab-1 [Mattoon et al., 2004; Scaltriti & Baselga, 2006].

and tumor progression [Bromberg, 2002].

[Bromberg, 2002; Haura et al., 2005].

progression [Bromberg, 2002].

al., 1998; McClellan et al., 1999].

2004; Uberall et al., 2008].

**3. ErbB receptors and cancer** 

system signaling network [Uberall et al., 2008].

**2.3.4 Src kinase pathway** 

immune function.

The EGF system signaling network in cancer becomes hyperactivated with a range of mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation) [Marmor et al., 2004; Salomon et al, 1995; Yarden & Sliwkowski, 2001b]. It is also contributes in proliferation, transformation, angiogenesis, migration and invasion [Holbro et al., 2003].

Fig. 1. ErbB receptors signalling.

#### **3.2 Expression of ErbB receptors in cancer**

Overexpression and structural alterations of EGFR are frequent in head, neck, esophageal, breast, lung, gastric, liver, kidney, colorectal, prostate, bladder and ovarian cancer [Moscatello et al., 1995; Yarden & Sliwkowski, 2001b; Uberall et al., 2008]. They associated with higher grade, disease progression, poor survival and resistance to radiotherapy and chemotherapy [Yarden & Sliwkowski, 2001b; Lurje & Lenz, 2009].

Overexpression of ErbB-2 is frequent in head, neck, breast, lung, pancreatic, esophageal, liver, colorectal, prostate, bladder, ovarian, endometrial and cervical cancer [Odicino et al.; Ross & Fletcher, 1998; Yarden & Sliwkowski, 2001b; Uberall et al., 2008]. It is an indicator of a more aggressive clinical behavior [Ross & Fletcher, 1998; Yarden & Sliwkowski, 2001b; Odicino et al., 2008].

Overexpression of ErbB-3 is frequent in head, neck, breast, gastric, liver, colorectal, prostate and ovarian cancer [Yarden & Sliwkowski, 2001b; Uberall et al., 2008]. Although ErbB-3 overexpression related with ErbB-2 positivity and lymph node involvement, a definitive relationship with survival has not been established [Lemoine et al., 1992; Gasparini et al., 1994; Bièche et al., 2003].

Overexpression of ErbB-4 is frequent in head, neck, lung and liver cancer [Yarden & Sliwkowski, 2001b; Uberall et al., 2008]. It is related with favorable prognosis in breast and bladder cancer [Suo et al., 2002; Memon et al., 2004; Barnes et al., 2005].
