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Abstract
The epidermal growth factor receptor (EGFR) and EGFR2 are members of ErbB family receptor tyrosine kinases (RTK{u2019}s), which are frequently overexpressed in breast cancer and thus have been validated as targets for tyrosine kinase inhibitors such as lapatinib drug. However, transactivation of the EGFR and EGFR2 tyrosine residues could be utilized via different cytokines stimulation such as interleukin-6 or -8 (IL-6 or IL-8), suppressing the effect of tyrosine kinase inhibitors. In the present study, we evaluated the effect of IL-6 and IL-8 (50 ng/ml and 100 ng/ml) on activation of the EGFR and EGFR2 in the SKBR3 breast cancer cell line. Moreover, we assessed the impact of IL-6 and IL-8-induced activation of the EGFR, EGFR2, ERK1/2, STAT3 and non-receptor tyrosine kinases signaling molecule Src by Western blot, 3D-spheroids formation and the invasive potential using BD Bio-Coat Matrigel Invasion chamber in the absence and presence of lapatanib drug. Our data indicated that the IL-6 and IL-8 transactivated the EGFR, EGFR2 at Tyr-845 and Tyr-Y1248 tyrosine kinases respectively upon stimulation for the SKBR3 breast cancer cell line. Interestingly, our results showed that IL-6 and IL-8-induced activation of EGFR and EGFR2 downstream signaling clues including (Src, ERK1/2 and STAT3). Whereby the lapatinib drug did not inhibit the signaling molecules stimulated by IL-6 and IL-8 at the specified time intervals when compared to control cells. On the other hand, the increase in number and size of tumor spheroid formation by SKBR3 is an indicator reflecting the impact of IL-6 and IL-8 in increasing the cell proliferation, in the presence of lapatinib drug when compared to control cells seeded in complete medium where the spheroid formation increased upon stimulation. On the other hand, the drug have shown to be lethal to control cells in the absence of stimulants