FOXO3a反馈上调人表皮生长因子受体3表达介导HER2^+乳腺癌细胞酪氨酸激酶抑制剂治疗耐受

Feedback Up-regulation of HER3 Expression Induced by FOXO3a Mediates TKI Resistance in HER2^+ Breast Cancer Cells

近年来,酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKI)类药物治疗HER2+乳腺癌进展迅速,但出现治疗耐受仍是迫切需要解决的问题。本研究采用TKI(AEE788、Lapatinib)处理HER2+乳腺癌细胞BT474和SKBR3,发现HER3在mRNA和蛋白质水平上的表达均上调。MTS及克隆形成实验结果显示,siRNA干扰HER3的表达能够显著抑制BT474、SKBR3细胞的增殖,表明干扰HER3可增强细胞对TKI的敏感性。为进一步考察TKI促进HER3表达的可能机制,Western印迹及免疫荧光检测发现,AEE788、Lapatinib能够上调FOXO3a的表达且促进其入核。干扰FOXO3a可逆转TKI对HER3的诱导作用,说明TKI通过激活FOXO3a上调HER3的表达。综上所述,FOXO3a反馈上调HER3表达介导HER2+乳腺癌细胞TKI治疗耐受。这一研究发现,为临床解决TKI治疗耐受提供一定的理论基础。

Great progress has achieved in tyrosine kinase inhibitors(TKI)treatment for HER2+breast cancer in recent years,but treatment resistance is still the problem needed to be solved.In this paper,treatment with TKI(AEE788,Lapatinib)resulted in up-regulation of HER3 in mRNA and protein levels in HER2+breast cancer cell lines,BT474 and SKBR3.MTS and clonogenic assays showed knockdown of HER3 with siRNA and treatment with AEE788 or lapatinib enhanced TKI-induced cell death,suggesting that silencing of HER3 expression increases the sensitivity of HEE2+breast cancer cells to TKI.To further explore the potential mechanism of the up-regulation of HER3 induced by TKI,Western blotting and immunofluorescence assays showed AEE788 and Lapatinib up-regulated the expression of FOXO3 a and promoted it into the nucleus.Interference with FOXO3 a reversed the induction of HER3 by TKI,indicating that TKI up-regulated HER3 expression by activating FOXO3 a.In conclusion,FOXO3 a induces up-regulation of HER3 to mediate TKI resistance in HER2+breast cancer cells.This study provides a theoretical basis for the clinical solution to TKI treatment resistance.