The Preliminary Study On The Function And Mechanism Of Annexin A2 In Gefitinib Resistance Of The Breast Cancer Cells

Triple-negative breast cancer(TNBC)is a subtype of breast cancer which is generally negative for the expression of estrogen receptor(ER)and progesterone receptor(PR)and human epidermal growth factor receptor 2(HER-2).Due to the lack of approved effective targets for hormonal therapy and anti-HER-2 treatment,TNBC has long been a challenge in the field of breast cancer treatment.Epidermal growth factor receptor(EGFR)may be as a therapeutic target for TNBC based on its high expression.But the clinical use of drugs such as EGFR inhibitors for the treatment of TNBC did not obtain the ideal effect.The majority of the TNBC patients have resistance to EGFR inhibitors which was intrinsic or acquired in the later treatment.The objective of this study was to preliminary discuss the mechanisms leading to EGFR inhibitors resistance.In this study,we used human breast cancer cell line MDA-MB-231 which do not express ER,PR and HER-2.At the same time,we used MCF-7 cell lines that was HER-2 positive.We found that MDA-MB-231 cells which express high levels of EGFR,were not sensitive to gefitinib.MDA-MB-231 breast cancer cells express high levels of Annexin A2,and a large number of studies have shown that the expression level of Annexin A2 is related to the proliferation,invasion and migration of tumor cells.In order to know if Annexin A2 expression levels is involved in the resistance of breast cancer cells to gefitinib,we reduced the expression level of Annexin A2 in MDA-MB-231 cells and overexpressioned Annexin A2 in MCF-7 cells with low levels of Annexin A2.The result showed that the sensitivity of breast cancer cells to gefitinib is correlated with the expression level of Annexin A2.When knocked down the expression of Annexin A2 in MDA-MB-231 cells,their sensitivity to gefitinib was increased.However,improving the expression of Annexin A2 in MCF-7 cells reduced their sensitivity to gefitinib.To further explore the mechanism of gefitinib resistance,we overexpressed different mutants of Annexin A2 in MCF-7 cells,which mimicking non phosphorylation state(AnxA2-Y23A)and constitutive phosphorylation state(AnxA2-Y23E)of Annexin A2.The result showed that the phosphorylation of Annexin A2 at Tyr23 significantly reduced the sensitivity of breast cancer cells to gefitinib.To sum up,these results suggest that Annexin A2 and its Tyr23 phosphorylation are one of the important factors that cause gefitinib resistance to breast cancer cells.