الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. Mammary carcinogenesis is a multistep process with transformation of normal ductal epithelial cells→ benign proliferative breast disease→ DCIS→ IDC. Women with benign breast disease could be prevented from developing IBC if we can exactly identify patients with which subtype of benign lesions will subsequently develop IBC and treat them.
The purpose of this study was to evaluate COX-2 expression in the successive steps of breast carcinogenesis and to determine its correlation with p53 and CD31 expression in invasive carcinomas of the breast. In this study, we tried to evaluate the role of COX-2, p53 and CD31 in the progression of breast cancer, and to correlate their expression with some clinicopathological and prognostic factors.
The present study included a total of 77 breast specimens, 4 with normal breast tissue, 5 with typical ductal hyperplasia, 11with DCIS, and 57 with infiltrating carcinoma (three of them were ILC and excluded from the results and discussed separately), selected from the files of the Department of Pathology, Sohag University Hospital and the Private Laboratories of Professor Dr. Marcille Naseem Guirguis.
The H & E stained sections of the 77 cases were evaluated and then DCIS were graded according to World Health Organization criteria into, 2/11(18%) were low grade, 3/11 (27%) were intermediate grade, and 6/11 (55%) were high grade. Also IDC were classified according to Elston and Ellis grading system into 6/54 (11%) were low grade, 29/54 (54%) intermediate, and 19/54 (35%) were high grade ductal carcinomas. Sections from these cases were Immunostained with COX-2, p53, and CD31 to detect their expression.
The clinicopathological criteria of the studied cases were as follows:
The mean age was 46, 50, 53, and 55 years for cases of ductal hyperplasia, DCIS, IDC, and ILC respectively. The mean age of the patients with IDC was 53 years (range 26–77 years). The tumor size was >2cm and ≤5cm in 23/54 (43%) cases, and >5cm in 31/54 (57%) of cases. Axillary lymph nodes were positive in 36/54 (67%) patients. IDC NST was the most common histological pattern 42/54 (77.8%). Lymphovascular space invasion was observed in 21/54 (39%) cases. Lymphocytic infiltrate was prominent in 14/54 (26%) of cases. Desmoplasia was prominent in 35/54 (65%) of cases.
COX-2 is a prostaglandin synthetase enzyme that converts arachidonic acid into pro-inflammatory prostaglandins, induced in inflammation and cancer. It seems to be involved in the processes of malignant transformation and tumor progression by affecting cell proliferation, mitosis, cell adhesion, apoptosis, immune surveillance, and angiogenesis. An elevated COX-2 level has been shown to correlate with a worse prognosis for patients with some types of tumors including breast cancer.
COX-2 expression was weak in 3/4 and moderate in 1/4 case of normal breast tissue, whereas it was moderate in 3/5, and weak in 2/5 cases of typical ductal hyperplasia of the breast. COX-2 was weak in 3/11(27.3%), moderate in 6/11(54.5%), and strong in 2/11(18.2%) of cases of DCIS. There was an increase in COX-2 expression with increasing grade of DCIS (P<0.05). COX-2 expression was weak in 11/54 (20.4%), moderate in 19/54 (35.2%), and strong in 24/54 (44.4%) cases of IDC. There was an increase in COX-2 expression with increasing grade of IDC. Also COX-2 expression appeared to increase progressively along the continuum of neoplastic changes from normal breast epithelium to IDC (P<0.01).
Current study showed statistically significant correlation between COX-2 expression and tumor size (P<0.05), tumor grade (P<0.002), lymphovascular invasion (P<0.03), and lymph node metastasis (P<0.02). However, no correlation was found between COX-2 and the age, lymphocytic infiltration, or desmoplasia.
P53 is a tumor suppressor gene that maintains genomic stability either by inducing cell cycle arrest or apoptosis. In ductal carcinomas, p53 gene is mutated with subsequent overexpression of p53 protein.
P53 expression was weak in 1/4 (25%), and negative in 3/4 (75%) cases of normal breast tissue. P53 expression was weak in 1/5 (20%) and negative in 4/5 (80%) of typical ductal hyperplasia. P53 was negative in all 2/2 (100%) grade I, positive in 2/3 (66.7%) grade II, and in all 6/6 (100%) grade III DCIS. There was an increase in p53 expression with increasing grade of DCIS (P<0.01). P53 was positive in 3/6 (50%) grade I, in 20/29 (69%) grade II, and in 17/19 (89.5%) grade III IDC. There was an increase in COX-2 expression with increasing grade of IDC (P<0.002). P53 expression appeared to increase progressively along the continuum of neoplastic changes from normal breast epithelium to IDC (P<0.01).
There was statistically significant correlation between p53 expression and tumor size (P<0.05), tumor grade (P<0.002), lymphovascular invasion (P<0.02), and lymphocytic infiltration (P<0.03). However, there was no significant correlation between p53 expression and age, lymph node metastasis or desmoplasia.
Angiogenesis is an important key step in tumor progression. Microvascular density, a surrogate marker of angiogenesis can be assessed by CD31 staining, which is a cell adhesion molecule.
The median MVD as assessed by CD31 expression in normal breast tissue, ductal hyperplasia, DCIS, and IDC was 10, 17, 19, and 66.5 respectively. This increase is only significant in the transition between DCIS and IDC (P<0.000). There was insignificant increase in MVD between different grades of DCIS (P = 0.17). But there was significant increase with increasing the grades of IDC (P < 0.01).
Pearson’s Correlation revealed positive correlation between COX-2 and P53 in DCIS and in IDC (r= 0.888, P <0.000 & r= 0.894, p<0.000 respectively), P53 and CD31 in DCIS and in IDC (r= 0.836, P <0.001 & r= 0.878, p<0.000 respectively), and COX-2 and CD31 in DCIS and in IDC (r= 0.900, P <0.000 & r= 0.881, p<0.000 respectively).
Conclusion
1. COX-2 expression increases progressively along the continuum from normal breast epithelium to invasive ductal carcinoma, so it may be involved in breast carcinogenesis and it may be a useful target for chemoprevention of breast cancer.
2. The up-regulation of COX-2 with increasing grades of both DCIS and IDC, size of tumor, presence of lymphovascular invasion, and/or presence of positive axillary lymph nodes metastasis in IDC indicates that COX-2 overexpression is a significant unfavorable prognostic factor in breast cancer, and provides selective criteria for COX-2 inhibitor combinations for invasive breast cancer therapy.
3. P53 expression shows progressive increase along the continuum of neoplastic changes from normal breast epithelium to invasive ductal carcinoma. So p53 may be involved in the progression of breast cancer, and may provide a clinically useful biomarker for estimating tumor aggressiveness.
4. P53 increases with increasing grades of both DCIS and IDC, size of tumor, presence of lymphovascular invasion, and/or prominent lymphocytic infiltration in IDC. So its elevation in breast carcinoma may reflect a more aggressive biological behavior.
5. The up-regulation of angiogenesis as assessed by CD31 expression with increasing grades of IDC may reflect that aggressive tumors are more capable of angiogenesis, and that angiogenesis is a poor prognostic sign for IDC.
6. A significant increase in angiogenesis occurs on transition from DCIS to IDC, and so anti-angiogenic factors can be used as new therapeutic strategies in order to prevent the progression of DCIS to invasive carcinoma.
7. P53 is likely to be involved in the regulation of COX-2 expression and COX-2 contributes to the regulation of angiogenesis with other proteins. So angiogenesis-based treatment protocols that target multiple proteins will have better results.
Recommendations
1. Studying the expression of COX-2, p53, and CD31 on a large number of cases of breast lesions, including large numbers of different types of infiltrating breast carcinomas e.g: lobular carcinoma.
2. Most of the normal, hyperplastic lesions and in situ carcinoma were adjacent to the invasive tumors and a further evaluation in patients with only these lesions in larger study is warranted.
3.Follow up of patients to emphasize the correlation between COX-2, p53, and CD31 expression and the patient survival and disease outcome.