ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor α expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells
ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor α expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells
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DOI：
10.1677/erc-07-0189
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Payen, Lea
中科院分区：
文献类型：
--
作者：
Honorat, Mylene;Mesnier, Aurelia;Payen, Lea
ABCC11（多药耐药蛋白8；MRP8）是一种质膜atp结合的盒式转运蛋白，由于其对氟嘧啶和外排甲氨蝶呤具有耐药性的能力，并通过其在该肿瘤中的表达，与乳腺癌的耐药有关。ABCC11在乳腺这一受激素调节的组织中的表达，以及该泵运输雌激素偶联物的能力，提示ABCC11的表达可能易受雌激素的调节。然而，目前对该基因的调控还一无所知。在本研究中，雌二醇（E-2）处理降低了雌激素受体(ER)- α阳性MCF7细胞中ABCC11 mRNA的表达，而E-2拮抗剂如ICI 182 780和他莫昔芬（TAM）则消除了E-2介导的下调。ABCC11的表达与er - α的表达在两种乳腺细胞系以及绝经后患者的两个独立肿瘤系列中均呈正相关。此外，ABCC11在暴露于TAM 72 h的MCF7细胞中表达上调，并在TAM抗性细胞系中过表达。tam耐药细胞的药物敏感性分析表明，它们也对5-氟尿嘧啶（5-FU）耐药，这与报道的ABCC11对该药物产生耐药性的能力一致。这些研究表明，ABCC11的表达受E-2的负调控，但在高表达er - α的乳腺癌中，ABCC11的表达较高。我们的研究结果支持了ABCC11在er - α阳性乳腺癌中的表达可能有助于降低对包括5-FU在内的化疗组合的敏感性。ABCC11可能是一个潜在的预测工具，用于选择抗TAM的er阳性乳腺癌的抗癌治疗。
ABCC11 (Multidrug resistance protein 8; MRP8), a plasma membrane ATP-binding cassette transporter, has been implicated in drug resistance of breast cancer by virtue of its ability to confer resistance to fluoropyrimidines and to efflux methotrexate, and by its expression in this tumor. Expression of ABCC11 in breast, a hormonally regulated tissue, as well as the pump's ability to transport estrogen conjugates, suggest the possibility that expression of ABCC11 may be susceptible to regulation by estrogen. However, nothing is currently known about regulation of this gene. In this study, estradiol (E-2) treatment reduced expression of ABCC11 mRNA in estrogen receptor (ER)-alpha-positive MCF7 cells, and E-2 antagonists such as ICI 182 780 and tamoxifen (TAM) abrogated E-2-mediated downregulation. ABCC11 expression was positively correlated with ER-alpha expression in both breast cell lines, and two independent series of tumors from postmenopausal patients. In addition, expression of ABCC11 was upregulated in MCF7 cells exposed to TAM for 72 h, and was overexpressed in TAM-resistant cell lines. Drug sensitivity analysis of the TAM-resistant cells indicated that they were also resistant to 5-fluorouracil (5-FU), consistent with the reported ability of ABCC11 to confer resistance to this agent. These studies indicate that ABCC11 expression is negatively regulated by E-2, but that ABCC11 expression is high in high-expressing ER-alpha breast cancers. Our findings support the notion that expression of ABCC11 in ER-alpha-positive breast cancers may contribute to decreased sensitivity to chemotherapy combinations that include 5-FU. ABCC11 may be a potential predictive tool in the choice of anticancer therapies in ER-positive breast cancers resistant to TAM.