الفهرس 
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Abstract
HSPs have been characterized as members of the molecular chaperones, group of proteins that play essential roles in the correct folding of a large proportion of cellular proteins.They participate directly in cell survival during hyperthermia by inhibiting programmed cell death and cell senescence. The transcription of HSP genes is regulated by transcription factor HSF1, that senses cellular exposure to stress and turns on rapid induction of HSPs
These properties of the HSPs appear to have been hijacked during malignant progression and aid in the development of cancer. HSP levels become elevated in a wide spectrum of malignant cells including mammary carcinoma cells. HSP27 and HSP70 appear to foster mammary tumorigenisis ,while HSP90 appears to play a key role in facilitating tumor progression by chaperoning the mutated and overexpressed oncogenes that fuel transformation and tumor progression. Indeed HSPs may contribute to the evolution of treatment resistant cell populations by permitting the emergence of variant proteins that can overcome the stresses of cancer therapy .Quercetin has been found to inhibit production of HSPs in several malignant cell lines, including breast cancer,
Our purpose was to study contribution of HSPs to the induction of necroptosis as a cansequence to irradiation in breast cancer cells, also to inspect the effect of HSPs inhibition on necroptosis.
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).
Group2: Cells were treated by Quercetin HSPs inhibitorat concentration 15 and 50 Mµl
Group3: 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:
• HSF-1 expression was significantly reduced in response to treatment by quercetin, while in the control group it was significantly increased in response to radiation exposure. Both HSP-70 and HSP-27 significantly increased in response to radiation in controls of both cell lines and to a lesser extent HSP-90 too.
• In MCF-7, caspase-8 was down-regulated except high radiation dose (10 Gy). while, in MDA cells, caspase-8 expression levels were up-regulated in response to all doses of radiation. Treatment with quercetin resulted in a significant up-regulation of caspase-8 expression levels in MDA cell lines that increased with increasing quercetin concentration. Concomitant treatment ofMDA cells by both radiation and quercetin resulted in significant up-regulation of caspase-8 expression.
• RIPK1 expression, was up-regulated in MCF7 cell line in response to radiation exposure .but is inhibited in MDA, While treatment by quercetin alone resulted in a significant dose-dependent up-regulation of RIPK1 expression in MCF7 cells but not in MDA cells. Upon the combined treatment of cells by both radiation and quercetin, MDA cells retained RIPK1 down-regulation through all radiation doses treatments, while MCF7 cells showed a significant up-regulation that increased with increasing quercetin concentration.
• RIPK3 expression, was uniformly up-regulated in both cell lines in response to radiation exposure . While treatment by quercetin alone resulted in a significant dose-dependent up-regulation of RIPK3 expression in MDA cells but not in MCF-7 cells. Upon the combined treatment of cells by both radiation and quercetin, both cell lines retained RIPK 3 up-regulation through all radiation doses treatments.
• MLKL expression, was up-regulated in both cell lines in response to radiation exposure through all doses. While treatment by quercetin alone resulted in a significantly dose-dependent up-regulation of MLKL expression in MDA cells not in MCF-7 cells. Upon the combined treatment of cells by both radiation and quercetin, MCF-7 cells retained MLKL down-regulation through radiation doses treatments, while MDA cells showed a significant up-regulation especially in high dose
• 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-231 cells. Treatment by quercetin alone resulted in a significant reduction in survival of MCF-7 cells at 15 uM and in MDA-231 starting at 50 uM. Exposure to both quercetin and radiation resulted in lower survival than radiation alone.