الفهرس 
Introduction
Etiology and Risk factors of breast cancerOnly 14 pages are availabe for public view
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Abstract
One of the most important molecular events that play an essential role in progression of significant percentage of breast cancer is the family of the human epidermal growth factor receptors (EGFR). Over expression of EGFRs was found to have prognostic and predictive value with subsequent development of a targeted treatment that is tumor selective. The most famous family member of EGFR is HER2, which is a target in Herceptin therapy in metastatic status and also in adjuvant therapy of breast cancer in the event of dysregulation as a result of gene amplification and resulting protein overexpression(Sassen et al. 2008).
The epidermal growth factor receptor (EGFR) family is a member of the ErbB family of tyrosine kinase receptors, which includes EGFR (ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) (Ferguson et al. 2003).
In this study we investigated the immunohistochemical expression of the EGFR family members in 336 specimens of invasive breast carcinoma. We also investigate the correlation between EGFR expression with different clinicopathological parameters involving (Age, size, grade, stage and lymph node metastasis, hormonal status and the proliferation index of tumors using the proliferative marker KI67).
Formalin-fixed paraffin-embeddedblocks of 336 female patients diagnosed as primary invasive breast carcinoma were obtained from the archives of the surgical pathology lap, Assiut university.
Manual tissue microarray (TMA) technology was used to construct three patches of TMA blocks for the 336 specimens.
Sections of 4μmthickness from each TMA paraffin blockwere cut and mounted.Immunohistochemical staining was performed using immune-perioxidase technique for HER1, HER2, HER3, HER4 and KI67 antibodies. Membranous expression of HER1 andHER2were assessed according to standard method (Herceptest method).Cytoplasmic expression of all EGFR was assessed using IHC (H score) score.KI67 was assessed, by counting the percentage of positive staining cells ”0-100 %”.
HER1
HER1 was expressed in invasive breast carcinoma cells, with both cytoplasmic and membranous staining pattern. Cytoplasmic expressionwas positive in 72.2% specimens.Membranous staining was positive in 20% of specimens.
Statistically significant inverse relationship was present between HER1 membranous expression and hormone receptor status ER (P<0.001), PR (P 0.007) and lymphocytic infiltrate(P 0.025). Inverse relation also found between both cytoplasmic and membranous expression of HER1 and LVI (P =0.057)&(P =0.038) respectively. Proportionate relationship was detected between membranous expression of HER1 and presence of tumor necrosis (P =0.001).
HER2
HER2 was over expressed in invasive breast carcinoma cells, with both cytoplasmic and membranous staining patterns. Cytoplasmic expression was positive in 94.3% ofspecimens while membranous expression was positive in18.6% of specimens.
Statistically significant inverse relationship was detected between cytoplasmic expression of HER2 and tumor grade (P =0.004), while significant positive relation was detected between its expression and ER and PR expression (P= 0.016) & (P=0.004) respectively. Statistically significant inverse relationship was detected between membranous expression of HER2 and ER status (P =0.002).
HER3
HER3 was expressed in invasive breast carcinoma cells, withonly cytoplasmic staining pattern 93.6% specimens.The only statistically significant inverse relationship was present betweenexpression of HER3 and LVI (P=0.044).
HER4
HER4 was expressed in invasive breast carcinoma cells with cytoplasmic staining pattern in 94.7% of specimens. The only statistically significant inverse relationship was present betweenexpression of HER4 and tumor grade (0.019).
Proliferation index(PI)
PI ranged from 0% to100% in the studied specimens.Statistically significant proportionate relationship was detected between KI67expression and histopathological grading of tumor (P =0.025) and presence of mitotic figures (P =0.026).
Relationship between the investigated biological markers in invasive duct carcinoma of the breast
Statistically significant weak positive correlation was present between cytoplasmic expression of HER1 and HER2 (r=0.258, p<0.001).
Statistically significant moderate positive correlation was present between cytoplasmic expression of HER1 and HER3 (r=0.401, p<0.001).
Statistically significant weak positive correlation was present between cytoplasmic expression of HER1 and HER4 (r=0.317, p<0.001).
Statistically significant weak positive correlation was present between cytoplasmic expression of HER2 and HER3 (r=0.351,p<0.001).
Statistically significant weak positive correlation was present betweencytoplasmic expression of HER2 and HER4(r=0.363, p<0.001).
Statistically significant weak positive correlation was present betweencytoplasmic expression of HER2 andexpression of ER (r=0.211, p<0.002).
Statistically significant weak positive correlation was present betweencytoplasmic expression of HER2 andexpression of PR (r=0.240, p<0.001).
Statistically significant moderate positive correlation was present betweencytoplasmic expression of HER3 and HER4(r=0.468, p<0.001).
As regard HER2 and HER3 heterodimers. Ninety percent (90%) of specimens that showed positive membranous expression of HER2 also expressed HER3 and that this heterodimerization was significantly inversely related to ER negative tumors (P=0.01).
Comparing specimens that showed positive membranous staining for bothHER1andHER2 (score 2and/or score3) with specimens that are negative to this co-expression, it was found that; the only significant positive association was present with tumor necrosis(P=0.04).