Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells
Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells
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DOI：
10.1677/erc-06-0016
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发表时间：
2007-06-01
影响因子：
3.9
通讯作者：
Kang, Keon Wook
中科院分区：
文献类型：
--
作者：
Choi, Hoo Kyun;Yang, Jin Won;Kang, Keon Wook
对他莫昔芬（TAM）的获得性耐药是乳腺癌患者的一个严重治疗问题。从化疗反应性乳腺癌细胞到化疗抗性癌细胞的转变主要伴随着多药耐药相关蛋白（MRP）表达的增加。在本研究中，发现TAM抗性MCF-7（TAMR-MCF-7）细胞比对照MCF-7细胞表达更高水平的MRP 2。使用MRP 2基因启动子的分子分析支持了TAMR-MCF-7细胞中MRP 2过表达中的姜烷X受体（PXR）的参与。虽然CCAAT/增强子结合蛋白β在TAMR-MCF-7细胞中持续过表达，但这可能不是MRP 2基因转录激活的原因。此外，磷脂酰肌醇3-激酶（P13-激酶）的基础活性在TAMR-MCF-7细胞中高于对照细胞。抑制P13激酶可显著降低TAMR-MCF-7细胞的PXR活性和MRP 2表达。总体而言，MRP 2诱导在TAM耐药乳腺癌中额外获得化疗耐药性中发挥作用。
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy- responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistance-associated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein beta was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (P13-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of P13-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.