FKBP51表达降低促进雌激素受体阳性乳腺癌他莫昔芬耐药机制初探

Effect of FKBP51 on tamoxifen resistance in estrogen receptor positive breast cancer

目的:初步探讨FK506结合蛋白51(FKBP51)在雌激素受体阳性(ER+)乳腺癌他莫昔芬耐药中的作用及分子机制。方法:采用ER+人乳腺癌MCF-7细胞建立对他莫昔芬耐药的MCF-7/TAMR细胞,MTT法检测他莫昔芬对MCF-7和MCF-7/TAMR细胞增殖的影响。Western blot检测FKBP51和蛋白激酶B(AKT)信号通路中相关蛋白在MCF-7和MCF-7/TAMR细胞中的表达情况。通过敲低或者过表达FKBP51,观察FKBP51对ER+乳腺癌细胞耐药性及AKT信号通路的影响。在ER+人乳腺癌组织标本中验证FKBP51表达情况。结果:成功建立MCF-7/TAMR细胞株。他莫昔芬对MCF-7和MCF-7/TAMR细胞增殖的抑制率均呈剂量依赖性,且对MCF-7细胞增殖的抑制率高于MCF-7/TAMR细胞(P<0.05)。Western blot结果显示,FKBP51在MCF-7/TAMR细胞中的表达低于MCF-7细胞,并且其表达水平的降低激活AKT信号通路的活性,促进乳腺癌细胞对他莫昔芬的耐药。同时,FKBP51在ER+他莫昔芬耐药人乳腺癌组织中表达水平低于他莫昔芬敏感人乳腺癌组织。结论:FKBP51表达水平降低促进ER+乳腺癌患者对他莫昔芬耐药,可能与激活细胞内AKT信号通路有关。

Objective:To explore the effect of FK506 binding protein 51(FKBP51)on tamoxifen resistance in estrogen receptor positive(ER+)breast cancer and its mechanism.Methods:The ER+human breast cancer MCF-7 cells was used to establish tamoxifen-resistant MCF-7/TAMR cell line.The effect of tamoxifen on the proliferation of MCF-7 and MCF-7/TAMR cells was detected by MTT method.Western blot was used to detect the expressions of FKBP51 and the associated proteins in AKT signaling in MCF-7 and MCF-7/TAMR cells.Results:The MCF-7/TAMR cell line was successfully established.The inhibitory rates of tamoxifen on the proliferation of two breast cancer cells were in a dose-dependent manner,which on MCF-7 cells was significantly higher than that on MCF-7/TAMR cells(P<0.05).Western blot results showed that the expression of FKBP51 in MCF-7/TAMR cells was significantly lower than that in MCF-7 cells.Compared with MCF-7 cells,AKT signaling increased in MCF-7/TAMR cells.Conclusion:lower FKBP51 expression promotes tamoxifen resistance in patients with ER+breast cancer,which may be related to activation of AKT signaling pathway.