ABCB1 and ABCC11 confer resistance to eribulin in breast cancer cell lines.
ABCB1 and ABCC11 confer resistance to eribulin in breast cancer cell lines.
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DOI：
10.18632/oncotarget.11727
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Ito KI
中科院分区：
文献类型：
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作者：
Oba T;Izumi H;Ito KI
本研究旨在阐明乳腺癌对艾日布林耐药的机制。建立了7个艾日布林耐药乳腺癌细胞系（MCF 7/E、BT474/E、ZR 75 - 1/E、SKBR 3/E、MDA-MB-231/E、Hs578T/E和MDA-MB-157/E）。与亲本细胞系相比，在所有艾日布林耐药细胞系中，ATP结合盒亚家族B成员1（ABCB 1）和亚家族C成员11（ABCC 11）的mRNA和蛋白质表达增加。当MCF7/E、BT474/E和MDA-MB-231/E细胞中ABCB 1或ABCC 11的表达被小干扰RNA抑制时，艾日布林敏感性部分恢复。此外，艾日布林耐药性通过抑制MCF7/E细胞中的ABCB 1和ABCC 11而相加地减弱。此外，外源ABCB 1或ABCC 11在HEK293 T细胞中的过表达赋予了对艾日布林的抗性。MCF 7/E和MDA-MB-231/E细胞对紫杉醇、阿霉素和氟尿嘧啶具有交叉耐药。ABCB 1的抑制部分恢复了紫杉醇和多柔比星的敏感性。通过抑制MCF7/E和MDA-MB-231/E细胞中的ABCC11诱导氟尿嘧啶敏感性的部分恢复。无论乳腺癌亚型如何，ABCB 1和ABCC 11都参与体外乳腺癌细胞中艾日布林耐药性的发展。因此，ABCB1和ABCC11表达可用作预测乳腺癌患者对艾日布林的反应的生物标志物。同时抑制ABCB 1和ABCC 11可能有助于增强艾日布林的抗肿瘤作用。
This study aimed to elucidate the mechanisms underlying the resistance of breast cancer to eribulin. Seven eribulin-resistant breast cancer cell lines (MCF7/E, BT474/E, ZR75-1/E, SKBR3/E, MDA-MB-231/E, Hs578T/E, and MDA-MB-157/E) were established. mRNA and protein expression of ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 11 (ABCC11) increased in all eribulin-resistant cell lines compared to the parental cell lines. When ABCB1 or ABCC11 expression was inhibited by small interfering RNA in MCF7/E, BT474/E, and MDA-MB-231/E cells, eribulin sensitivity was partially restored. Moreover, eribulin resistance was attenuated additively by inhibiting ABCB1 and ABCC11 in MCF7/E cells. Additionally, overexpression of exogenous ABCB1 or ABCC11 in HEK293T cells conferred resistance to eribulin. MCF7/E and MDA-MB-231/E cells showed cross-resistance to paclitaxel, doxorubicin, and fluorouracil. Inhibition of ABCB1 partially restored paclitaxel and doxorubicin sensitivity. Partial restoration of fluorouracil sensitivity was induced by inhibiting ABCC11 in MCF7/E and MDA-MB-231/E cells. Both ABCB1 and ABCC11 are involved in the development of eribulin resistance in breast cancer cells in vitro regardless of the breast cancer subtype. Thus, ABCB1 and ABCC11 expression may be used as a biomarker for predicting the response to eribulin in patients with breast cancer. Concomitant inhibition of ABCB1 and ABCC11 might help enhance the antitumor effects of eribulin.