**4. ErbB receptors and endometrial cancer**

#### **4.1 Endometrial cancer classification**

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 II EC overexpress genes involved in the regulation of the mitotic spindle checkpoint and associated with aneuploidy and aggressive clinical behavior (STK15, BUB1, CCNB2) [Moreno-Bueno et al., 2003; Risinger et al., 2003 Hecht & Mutter, 2006]. It is also associated with mutations in p53 gene, inactivation of p16, ErbB-2 amplification/overexpression and decreased expression of E-cadherin [Hetzel et al., 1992; Tashiro et al. 1997; Lax et al., 2000; Holcomb et al., 2002; Lax, 2004; Santin et al., 2005; Hecht & Mutter, 2006; Grushko et al., 2008; Bansal et al., 2009].

#### **4.2 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].

a more aggressive clinical behavior [Ross & Fletcher, 1998; Yarden & Sliwkowski, 2001b;

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.,

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

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

1. Type I EC, represents the majority of sporadic EC cases (70-80%). It is usually well differentiated and endometrioid in histology [Bokhman, 1983; Lax, 2004 Doll et al., 2008]. It is estrogen-related, usually arises from endometrial hyperplasia, has less aggressive clinical course and favorable prognosis [Bokhman, 1983; Sherman et al., 1997; Doll et al., 2008]. Type I EC overexpress genes hormonally regulated during the menstrual cycle and involved in endometrial homeostasis (MGB2, LTF, END1, MMP11) [Moreno-Bueno et al., 2003; Risinger et al., 2003]. It is also associated with defects in DNA mismatch repair, microsatelite instability MLH1/MSH6 and specic mutations in PTEN, K-ras and β-catenin genes [Basil et al., 2000; Lax et al., 2000; Lax, 2004; Hecht &

2. Type II EC, represents the minority of sporadic EC cases (10-20%). It is poorly differentiated and usually papillary serous or clear cell in histology [Bokhman, 1983; Lax, 2004 Doll et al., 2008]. It is not estrogen-related, arises from atrophic endometrium, has aggressive clinical course and propensity for early spread and poor prognosis

Type II EC overexpress genes involved in the regulation of the mitotic spindle checkpoint and associated with aneuploidy and aggressive clinical behavior (STK15, BUB1, CCNB2) [Moreno-Bueno et al., 2003; Risinger et al., 2003 Hecht & Mutter, 2006]. It is also associated with mutations in p53 gene, inactivation of p16, ErbB-2 amplification/overexpression and decreased expression of E-cadherin [Hetzel et al., 1992; Tashiro et al. 1997; Lax et al., 2000; Holcomb et al., 2002; Lax, 2004; Santin et al., 2005; Hecht & Mutter, 2006; Grushko et al.,

**4.2 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.,

bladder cancer [Suo et al., 2002; Memon et al., 2004; Barnes et al., 2005].

[Bokhman, 1983; Abeler & Kjorstad, 1991; Goff et al, 1994].

**4. ErbB receptors and endometrial cancer** 

**4.1 Endometrial cancer classification** 

classified into 2 types [Bokhman, 1983]:

Mutter, 2006; Bansal et al., 2009].

1994; Niikura et al., 1996; Ejskjaer et al., 2007].

2008; Bansal et al., 2009].

Odicino et al., 2008].

1994; Bièche et al., 2003].

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. 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 [Morrison et al., 2006; Konecny et al., 2009].

Although, ΕrbB-2 amplification/overexpression is more common in patients with type II EC, the exact frequency remains controversial. 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 [Santin et al., 2005; Morrison et al., 2006; Slomovitz et al., 2008; Grushko et al., 2008; Konecny et al., 2009;]. 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 [Morrison et al., 2006; Grushko et al., 2008; Konecny et al., 2009]. ΕrbB-2 overexpression especially in type II EC, is an indicator of a highly aggressive disease and a poor overall survival [Lukes et al., 1992; Santin et al., 2005; Morrison et al., 2006; Odicino et al., 2008].

ErbB-3, in endometrium, is localized to surface epithelial cells [Prigent et al., 1992; Srinivasan et al., 1999 Ejskjaer et al., 2005]. It is located to the cytoplasm, with membrane staining in a minority of samples [Srinivasan et al., 1999; Ejskjaer et al., 2007].

The clinical significance of ErbB-3 has not been studied well in EC [Srinivasan et al., 1999; Androutsopoulos et al., 2006; Ejskjaer et al., 2007; Adonakis et al., 2008].

ErbB-4, in endometrium, is localized to epithelial and stromal cells [Srinivasan et al., 1999; Chobotova et al., 2005; Ejskjaer et al., 2005]. It is located to the cytoplasm, with membrane staining in a minority of samples [Srinivasan et al., 1999; Ejskjaer et al., 2007;].

The clinical significance of ErbB-4 has not been studied well in EC [Srinivasan et al., 1999; Androutsopoulos et al., 2006; Ejskjaer et al., 2007; Adonakis et al., 2008].

#### **4.3 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.

#### **4.3.1 Anti-ErbB monoclonal antibodies (MoAbs)**


3. There is a new class of Anti-ErbB MoAb (pertuzumab) that prevent receptor heterodimerization [Baselga & Arteaga, 2005].

#### **4.3.2 ErbB-specific tyrosine kinase inhibitors (TKIs)**

TKI block the binding of adenosine triphosphate to the intracellular domain of EGFR (gefitinib, erlotinib) or EGFR and ErbB-2 (lapatinib) and blocks ErbB activity and subsequent intracellular signaling [Baselga & Arteaga, 2005; Lurje & Lenz, 2009].

#### **4.3.3 Effectiveness of ErbB-targeted therapies**

Overall response rate to these drugs is modest, unless they are associated with chemotherapy or radiotherapy [Baselga & Arteaga, 2005]. ErbB-targeted therapies have not been clinically tested in type II EC [Konecny et al., 2009]. Preclinical data suggest that ErbBtargeted therapies may be clinically active in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression [Villella et al., 2006; Jewell et al., 2006; Konecny et al., 2008; Santin et al., 2008; Vandenput et al., 2009; El-Sahwi et al., 2010;].

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.

#### **5. 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.

#### **6. References**


3. There is a new class of Anti-ErbB MoAb (pertuzumab) that prevent receptor

TKI block the binding of adenosine triphosphate to the intracellular domain of EGFR (gefitinib, erlotinib) or EGFR and ErbB-2 (lapatinib) and blocks ErbB activity and subsequent

Overall response rate to these drugs is modest, unless they are associated with chemotherapy or radiotherapy [Baselga & Arteaga, 2005]. ErbB-targeted therapies have not been clinically tested in type II EC [Konecny et al., 2009]. Preclinical data suggest that ErbBtargeted therapies may be clinically active in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression [Villella et al., 2006; Jewell et al., 2006; Konecny et al.,

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

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

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