MAPK/ERK信号通路在逆转乳腺癌内分泌治疗耐药中的作用

Role of MAPK/ERK signaling pathway in reversing endocrine resistance of breast cancer

目的探讨丝裂原活化蛋白激酶(MAPK)/细胞外调节蛋白激酶(ERK)信号通路在逆转乳腺癌内分泌治疗耐药中的作用。方法采用人乳腺癌细胞系MCF-7和T47D分别建立他莫昔芬治疗耐药细胞株MCF-7/TAMR和T47D/TAMR。分析MCF-7细胞与MCF-7/TAMR细胞、T47D细胞与T47D/TAMR细胞增殖能力和MAPK/ERK信号通路分子表达情况的差异。分析丝裂原活化蛋白激酶激酶(MEK)抑制剂U0126抑制MAPK/ERK信号通路后,对MCF-7/TAMR和T47D/TAMR细胞增殖的抑制作用、细胞周期分布以及转录因子表达的影响。结果与MCF-7细胞和T47D细胞比较,MCF-7/TAMR细胞和T47D/TAMR细胞的增殖速度显著加快(P<0.05),克隆形成能力显著增强(P<0.0001),MAPK/ERK信号通路分子[ERK、磷酸化细胞外调节蛋白激酶(pERK)和c-MYC]表达量显著增高。采用MEK抑制剂U0126抑制MAPK/ERK信号通路后,MCF-7/TAMR细胞和T47D/TAMR细胞的增殖速度显著减慢(P<0.0001),细胞周期发生停滞,MAPK/ERK信号通路的转录因子类固醇受体共激活因子(SRC-1)、E26转录因子-2(ETS-2)和c-JUN基因的相对表达量明显降低(P<0.01)。结论抑制MAPK/ERK通路可逆转乳腺癌细胞的内分泌治疗耐药,或可为制定内分泌治疗耐药乳腺癌患者的治疗方案提供新的思路。

Objective To investigate the role of mitogen-activated protein kinase(MAPK)/extracellular regulated protein kinase(ERK)signaling pathway in reversing endocrine resistance of breast cancer.Methods Tamoxifen-resistant breast cancer cell lines,MCF-7/TAMR and T47D/TAMR,were established by human breast cancer cell lines,MCF-7 and T47D.The differences of cell proliferation and the expression of related MAPK/ERK signaling pathway molecules between MCF-7 and MCF-7/TAMR,T47D and T47D/TAMR were investigated.The suppressive effect of mitogen-activated protein kinase(MEK)inhibitor U0126 on MAPK/ERK signaling pathway in MCF-7/TAMR and T47D/TAMR was observed through the analysis of cell proliferation,cell cycle and transfactor expression.Results Compared with naïve MCF-7 or T47D cells,the proliferation and colony formation were increased(P<0.05,P<0.0001),and the expression of related MAPK/ERK signaling pathway molecules[phosphorylated extracellular regulated protein kinase(pERK),ERK and c-MYC]was strongly increased.Suppressing MAPK/ERK signaling pathway by MEK inhibitor U0126,the growth of MCF7/TAMR or T47D/TAMR was decreased(P<0.0001),and cell cycle was arrested.The relative gene expression of transcription factors,steroid receptor coactivator-1(SRC-1),E26 oncogene homolog-2(ETS-2)and c-JUN,and the expressions of their proteins were decreased by MEK inhibitor U0126(P<0.01).Conclusions The inhibition of MAPK/ERK signaling pathway could reverse the endocrine resistance of breast cancer cells,which can provide a reference for the treatment of patients with endocrine resistant breast cancer.