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

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。

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

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 FOXO3a and promoted it into the nucleus. Interference with FOXO3a reversed the induction of HER3 by TKI, indicating that TKI up-regulated HER3 expression by activating FOXO3a. In conclusion, FOXO3a 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.