الفهرس 
Introduction
Breast cancerOnly 14 pages are availabe for public view
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Abstract
Breast cancer is one of the most common types of malignancies in women and is responsible for almost 22% of all female cancers. Like other tumors, breast cancer is a disease with a complex, heterogeneous genetic and biochemical background. No single genomic or metabolic condition can be regarded as decisive for its formation and progression. However, few key players can be pointed out among them is p53 tumor suppressor gene, which is the most frequently mutated gene in human malignancies.
One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. Apoptosis is controlled by the Bcl-2 family proteins, which include both anti- and pro-apoptotic proteins. Execution of apoptosis is mediated by a group of cysteine aspartic acid-specific proteases (caspases).
Recently, p53 has added the ability to mediate metabolic changes in cells through the regulation of energy metabolism and oxidative stress to its repertoire of activities.
The present study was carried out in the Department of Biochemistry, Faculty of Medicine, Assiut University and Faculty of pharmacy, Al-Azhar University, Assiut. Our study included 40 specimens of primary breast carcinoma in addition to 10 non-cancerous (marginal) samples as controls. They were classified into four groups (control, grade I, grade II and grade III). All tissue samples were obtained from the Department of Surgical Oncology, South Egypt Cancer Institute, Assiut University in the period from March 2013 until January 2015.
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Summary and conclusion
The present study evaluated the following biochemical parameters:
- Investigation of mutp53 and GAPDH expression levels were carried out by western blotting.
- Detection of changes in caspase-3 and Bcl-2 mRNA expression were carried out by RT-PCR.
- Lipid peroxidation as evidenced by formation of (MDA), level of nitrite and nitrate as an index of endogenous production of NO, SOD activity and tissue level of GSH, were assayed by colorimetric procedures.
The results of the current study showed:
- Overexpression of mutp53 in all grades of breast cancer in comparison to normal tissues indicating that p53 mutations can result in loss of p53 tumour suppressive function. There also was a positive relation between p53 overexpression and tumor grade suggesting the involvement of mutp53 in tumor progression.
- Overexpression of GAPDH in all grades of breast cancer in comparison to normal tissues indicating that GAPDH as a glycolytic enzyme might play a crucial role in cancer pathogenesis. Additionally, there was a positive relation between GAPDH overexpression and tumor grade suggesting that GAPDH may be used as an indicator for poor prognosis in breast cancer patients.
- The expression of caspase-3 mRNA was decreased in all grades of breast cancer patients in comparison to the controls, showing an inverse relation between caspase-3 expression and the tumor grade indicating that caspase-3 lower expression may contribute to tumour progression.
- Overexpression of Bcl-2 mRNA in all grades of breast cancer patients in comparison to the controls. The expression of Bcl-2 was gradually increased from grade 1 (low grade) until reached its maximum level at grade 3 (high grade), indicating that there was a positive relation between
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Bcl-2 mRNA overexpression and tumor grade suggesting the
involvement of Bcl-2 in tumor progression.
- Lipid peroxidation by measuring MDA and the tissue level of NO were significantly elevated in all grades of breast carcinoma when compared to the normal tissues, showing a positive relation with tumour grades.
- The activity of antioxidant SOD and tissue level of GSH were significantly decreased in cancer tissues compared with the normal breast tissues, showing a negative relation with tumour grades.
Conclusion
Regarding our clinical, molecular and biochemical findings associated
with breast cancer, we concluded that:
Mutp53 was seen in all grades of breast cancers, suggesting that p53 gene alteration can occur in the earliest phase of breast cancer and that alteration is maintained during tumor progression.
p53 mutation might be associated with an aggressive tumor phenotype, suggesting that mutant p53 could gain of tumor-driving role in breast cancer that promotes tumor growth and progression.
Our findings that mutp53 might be associated with an aggressive tumor phenotype provide an excellent example of how a gene mutations in tumor cells can transform an agonistic relationship into an antagonistic relationship. In this case, p53 mutation transforms a signaling network with tumor-suppressing functions into a network with oncogenic potential to promote tumor growth and progression.
p53 mutation could not only result in loss of tumor suppressive function of wild-type p53 but also could exert a dominant-negative effects over the other functions of wild type p53 mainly, its
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Summary and conclusion
apoptotic role, its role in metabolic regulation (glycolysis) and its
response to oxidative stress.
Moreover, our demonstration that mutp53 might be associated with metabolic changes in breast cancer cells further extends our understanding of the molecular mechanisms of mutp53 in cancers.
GAPDH could have a predicting role as an indicator for poor prognosis in breast cancer patients.
The dramatic increase in GAPDH expression might be coupled with the rapid growth and invasiveness of cancer cells, suggesting a role for GAPDH in cancer pathogenesis and progression. Based on this hypothesis, artificial suppression of the key reaction in glycolysis would have a therapeutic importance as a novel strategy to control human cancers.
Bcl-2 up-regulation and caspase-3 down-regulation and/or deficiency may be a mechanism that contributes to breast carcinogenesis by rendering breast cancer cells resistant to apoptosis and thus may affect the outcome and prognosis of the disease.
Changes in breast tissue contents of MDA, NO, GSH and SOD activity suggesting that reactive oxygen species play an important role in breast cancer progression, so antioxidants are recommended to be used as adjuvant therapy in the treatment of breast cancer patients.
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Recommendations:
Further studies are necessary to comprehend and confirm the effect of p53 mutation in human cancers and ascertain the relative contributions of each of the functional properties of p53, i.e. control of cell cycle, apoptosis and metabolic regulation, in tumorigenesis. The outcome of these studies can provide a novel and promising anti-cancer therapeutic approach. Furthermore, we recommended more advanced research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions. Thus could opening a new window for therapeutic opportunities.
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