Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2.
Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2.
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DOI：
10.1158/0008-5472.596.65.2
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Y. Imai;E. Ishikawa;Sakiyo Asada;Y. Sugimoto
中科院分区：
文献类型：
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作者：
Y. Imai;E. Ishikawa;Sakiyo Asada;Y. Sugimoto
乳腺癌耐药蛋白(BCRP)/ABCG2通过将化疗药物(如7-乙基-10-羟基喜树碱(SN-38)、米托蒽酮和拓扑替康)泵出细胞，介导对化疗药物的同时耐药。我们以前报道过BCRP转运硫酸盐雌激素。在本研究中，我们发现在生理水平上，雌激素显著降低雌激素反应和雌激素受体α(ERpha)阳性的人乳腺癌MCF-7细胞中内源性BCRP的表达，但在雌激素不反应的人癌细胞中没有。17β-雌二醇(E(2))在BCRP转导的雌激素反应性和ERpha阳性的MCF-7(MCF-7/BCRP)和T-47D细胞中也显著降低外源性BCRP的表达，但在BCRP转导的雌激素非反应性的MDA-MB-231和SKOV-3细胞中不显著。E(2)可显著增强SN-38对MCF-7/BCRP细胞的细胞毒作用，但对长春新碱无明显作用，并可增加MCF-7和MCF-7/BCRP细胞对拓扑替康的摄取。雌激素拮抗剂他莫昔芬可部分逆转E(2)介导的BCRP下调，ERα小干扰RNA作用于MCF-7/BCRP细胞可阻断E(2)介导的BCRP下调，提示E(2)与ERα的相互作用是BCRP下调所必需的。E(2)不影响MCF-7细胞内源性BCRP mRNA水平，也不影响MCF-7/BCRP细胞外源性BCRP mRNA水平。对MCF-7/BCRP细胞的脉冲追逐标记实验结果表明，E(2)介导的BCRP下调可能是蛋白质生物合成和成熟减少，而不是蛋白质周转改变的原因。这些数据表明，雌激素通过新的转录后机制下调BCRP的表达。这是第一次报道小分子可以影响细胞中BCRP蛋白的表达，因此可能有助于建立调节BCRP表达的新策略。
Breast cancer resistance protein (BCRP)/ABCG2 mediates concurrent resistance to chemotherapeutic agents, such as 7-ethyl-10-hydroxycamptothecin (SN-38), mitoxantrone, and topotecan, by pumping them out of cells. We previously reported that BCRP transports sulfated estrogens. In the present study, we show that at physiologic levels, estrogens markedly decrease endogenous BCRP expression in the estrogen-responsive and estrogen receptor alpha (ERalpha)-positive human breast cancer MCF-7 cells, but not in estrogen-nonresponsive human cancer cells. 17 beta-Estradiol (E(2)) also significantly reduces exogenous BCRP expression, driven by a constitutive promoter, in BCRP-transduced estrogen-responsive and ERalpha-positive MCF-7 (MCF-7/BCRP) and T-47D cells, but not in BCRP-transduced estrogen-nonresponsive MDA-MB-231 and SKOV-3 cells. E(2) potentiates the cytotoxicity of SN-38, but not vincristine, in MCF-7/BCRP cells significantly, and increases cellular topotecan uptake in MCF-7 and MCF-7/BCRP cells. Antiestrogen tamoxifen partially reverses E(2)-mediated BCRP down-regulation in MCF-7 and MCF-7/BCRP cells and treatment of MCF-7/BCRP cells with an ERalpha small interfering RNA abolished E(2)-mediated BCRP down-regulation, suggesting that interaction of E(2) and ERalpha is necessary for BCRP down-regulation. E(2) does not affect endogenous BCRP mRNA levels in MCF-7 cells or exogenous BCRP mRNA levels in MCF-7/BCRP cells. The results from pulse-chase labeling experiments with MCF-7/BCRP cells suggest that decreased protein biosynthesis and maturation, but not alterations in protein turnover, might underlie E(2)-mediated BCRP down-regulation. These data indicate that estrogen down-regulates BCRP expression by novel posttranscriptional mechanisms. This is the first report of small molecules that can affect BCRP protein expression in cells and may therefore assist in establishing new strategies for regulating BCRP expression.