الفهرس 
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Abstract
Incidence of breast cancer, as the most frequent cancer in women, has globally increased in recent years. Therefore, breast cancer is the main reason of cancer-related deaths of women worldwide. Family history, gender, age, genetics, bad lifestyle are risk factors for breast cancer. Conventional treatments available for breast cancer include surgery, chemotherapy, radiation therapy, hormonal therapy, or combination therapy. The accurate and early non-invasive detection of malignant disease is an important factor in the treatment and prognosis of a cancer patient. Early detection of the disease is a key to beast breast cancer successful treatment at early stages.
Radiotherapy is one of the best therapeutic choices for cancer treatment. Cellular responses to ionizing radiation produce a spectrum of effects ranging from growth arrest to cell death and senescence. The proportional reduction of loco regional recurrences with radiation therapy following surgery is, for most indications, " ~ "75%, with a dose–effect relationship for local control, thereby increasing the importance of optimizing loco regional treatments to obtain definitive cancer cure.
Cancer cells whose DNA is damaged beyond repair stop dividing and die. Thus, identifying the imp ortance of radiation induced cell death and further mechanisms involved has potential clinical implications for improving outcomes with radiation therapy, whereas, the efficancy of this therapeutic approach is significantly limited by resistance to tumor cell killing after exposure to ionizing radiation.
HSPs are a class of evolutionarily conserved proteins that increase in some pivotal conditions, such as radiations, heavy metals, oxidative stress, toxins, trauma, and chemotherapy. In normal cells without any stress condition, HSPs act as chaperons and maintain cellular protein hemostasis, but recently, some evidence have indicated that the elevation of the HSPs level is coordinated with metastasis of tumors, suggesting that HSPs might be used as a therapeutic strategy in tumor suppression. Quercetin is an efficient inhibitor of HSPs, and act through the inhibition the HSF-1 expression.
Autophagy is an intracellular catabolic mechanism that involves the degradation and recycling of cytoplasmic components, such as malfunctioning proteins or damaged organalles, to maintain cellular homeostasis. HSPs and HSF1 were shown to be required in autophagosome formation. In human breast carcinoma cells, exposure to chemotherapeutic agents increased autophagy that was prevented by knockdown of HSF1. Also, autophagy activating agent result in HSF1 activation and HSPs overexpression.
Our purpose was to explore whether autophagic cell death contributes to radiation –induced cell death in breast cancer. Also, to explore the interaction between the autophagic and heat shock response pathways in response to radiation damage.
The present study is an in vitro study employing the human breast cancer MCF-7 and MDA-MB-231 cell culture
Human BC cell lines MCF-7 and MDA-MB-231 culture, each of which was divide into four groups: group 1, Cells were exposed to radiation (at doses 4, 6, 8 and 10 Gy). group 2, Cells were treated by Quercetin HSPs inhibitor at concentration 15 and 50 Mμl group 3, Cells were exposed to a combination of Quercetin at concentration 15 and 50 Mμl and radiation (at doses 4, 6, 8 and 10 Gy). group 4, Cells were grown without treatment by Quercetin or radiation.
Our results showed that, in absence of quercetin, both cell lines showed up-regulation of HSF-1 expression in response to radiation, but MCF-7 showed a more dose dependent pattern than MDA-MB-231 cells. Upon treatment by 15 μΜ of quercetin, MCF-7 cells showed a much lower down-regulation of HSF-1 expression than MDA-MB-231 cells, however, at 50 μΜ concentration both cell lines showed a comparable degree of HSF-1 inhibition. Both HSP-70 and HSP-27 significantly increased in response to radiation in both cell lines and to a lesser extent HSP-90 too. Treatment by quercetin resulted in a significant dose dependent up-regulation of PTPN13 expression in MCF-7 cells more than MDA-MB-231 cell. Combination treatment of quercetin and radiation resulted in down regulation of PTPN13 expression at 15μM while up regulation at 50 μM quercetin. BIRC2 expression in MDA-MB-231 was up-regulated at lower radiation doses (4 and 6 Gy), while higher radiation doses resulted in its partial inhibition. While, in MCF-7 cells, BIRC2 was down-regulated in response radiation at doses (6 and 8 Gy). Quercetin treatment resulted the dose dependent up-regulation of BIRC2 expression in the two cell lines. In absence of radiation with treatment by quercetin at 15μΜ, BECLIN1 expression was down-regulation in MCF-7 cells, while MDA-MB-231 cells showed a significant up-regulation. But upon treatment with quercetin at 50μΜ, both cells showed an up-regulation, but MDA-MB-231 more than MCF-7. While, in MDA-MB-231 cells a down-regulation in response to higher radiation at doses (8 and 10 Gy). Meanwhile, in the different study groups both cell lines showed a comparable degree of SNARE inhibition in response to radiation. Exposure to radiation resulted in a significant decrease in survival in both cell lines in a dose-dependent manner, with MCF-7 showing significantly lower survival than MDA-MB-231 cells. Treatment by quercetin alone resulted in a significant reduction in survival of MCF-7 cells at 15 μM and in MDA-MB-231 starting at 50 μM. Exposure to both quercetin and radiation resulted in synergentic effect appeared in the reduction of survival of cells more than exposure to radiation alone.