الفهرس 
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Abstract
Breast cancer remains the most common cancer and most common cause of cancer-related mortality among women worldwide and its incidence is rising, especially in developing countries, where the disease poses a major health care challenge. In Egypt breast cancer incidence rates continue to increase, despite of the well-documented reductions in mortality from breast cancer during the past two decades. Death rates are falling owing to to earlier diagnosis, better surgical and radiotherapy techniques, and improved systemic therapies.
The causes of breast cancer are not fully known. However, epidemiological studies have identified many risk factors, which increase the chance of a female developing breast cancer. Many of these factors form the basis for breast cancer risk assessment tools. A “risk factor” of breast cancer is anything that increases the risk of developing breast cancer. Many of the most important risk factors of breast cancer are beyond control (non- modifiable) such as age, reproductive factors, family history of breast disease and genetic pre-disposition which do account for increased risks of breast cancer. However there are some risk factors that are modifiable (preventable) such as overweight, physical inactivity, cigarette smoking and alcohol consumption.
One of the aims of the present study was to assess some non- modifiable risk factors of breast cancer, such as age, menopausal status, family history of breast cancer and BRCA1 gene mutation. BRCA1 gene mutation were investigated in forty-five breast cancer females and thirty apparently healthy females. The relative risk was estimated according to age, menopausal status and family history. The results of the present study revealed that the relative risk of breast cancer is associated with increased age. The results also showed that the post-menopausal females has more increased risk for the development of breast cancer compared to pre-menopausal females. In addition, the present study revealed a significant increased risk of breast cancer development in females having BRCA1 mutation, as well as, the females with BRCA1 mutation and with age more than 40 years has increased risk of developing breast cancer than females with age less than 40 years. In the present study, the most frequent BRCA1 mutation was 5382insC followed by C61G and 185 delAG mutations.
On the other hand, optimal management of breast cancer can be achieved through understanding of tumor biology and genetics.The aim of systemic therapy in breast cancer is to palliate symptoms, control disease, and improve overall survival, while minimising the toxicity of treatment. Chemotherapy treatment uses medicine to weaken and destroy cancer cells in the body including cells at the original cancer site and any cancer cells that may have spread to another part of the body. Combination adjuvant chemotherapy reduces the relative risk of death from breast cancer by about a third, with the absolute risk reduction depending on the risk of relapse. FAC protocol is the regimen that was used in the treatment of the breast cancer patients enrolled in the present study.
One of the mechanisms through which cancer development could be controlled is autophagy. This process exerts different effects during the stages of cancer initiation and progression due to the occurring superimposition of signalling pathways of autophagy and carcinogenesis. Currently, the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in cancer cells are not fully understood but are progressively revealed. On the other hand, defects in apoptosis may lead to increased resistance to chemotherapy, radiotherapy, and other therapies. Therefore, induction of autophagic cell death may be an ideal approach in these resistant cancers therapies.
The other aim of the present study was to understand the major issues surrounding the controversial role of autophagy and the role of apoptosis in response to FAC regimen. Therefore, serum levels of autophagic biomarkers, Beclin 1 and LC3 concentrations was measured in forty- five breast cancer patients, as well as the serum levels of apoptosis biomarkers Bcl-2 and Caspase-3 before and after chemotherapy.
Meanwhile, the results revealed that chemotherapy causes the elevation in serum concentration levels of the autophagic biomarkers proteins Beclin 1 and LC3. Also, the study revealed a significant decrease in serum concentration levels of Bcl-2 and significant elevation in Caspase-3 concentration levels. These results, demonstrates the activation of autophagy and apoptotic machineries. Therefore, the present study concludes the involvement of autophagic and apoptotic machineries activation in response to FAC chemotherapy. However, it might be considered that autophagy is activated as a protective mechanism to mediate the acquired resistance phenotype of some cancer cells during chemotherapy or as a death executioner to induce autophagic cell death. Since autophagy is considered primarily as a cell survival mechanism, as well as it may act as an initiator of cell death. Thus, autophagy is shown to precede apoptosis or act in parallel with this cellular process in addition to be an alternative mechanism to cell death when apoptosis is inhibited.
Notably, a significant association between the 5382insC BRCA1 mutation and autophagy and apoptosis mechanisms was demonstrated in the present study by the decreased levels of serum LC3 and Bcl-2 in mutant breast cancer patients, suggesting the involvement of BRCA1 mutation in autophagy and apoptosis induction.
In conclusion, the present work reflected the magnitude and involvement of risk factors of breast cancer emphasizing in BRCA1 gene mutation and its genotypes. Additionally, the present work provides new insights into the machinery of autophagy after chemotherapy treatment in breast cancer, as well as the apoptotic machinery. Also, more lights were thrown in the association between BRCA1 mutation and autophagy and apoptosis mechanisms. Although, the results revealed the lack of correlation between Bcl-2 and Beclin 1 serum levels, the crosstalk between autophagy and apoptosis cannot be denied. The crosstalk between autophagy and apoptosis was argued and cleared out according to the involvement of their core proteins.