Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines
Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines
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DOI：
10.1096/fj.06-7990com
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发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Clarke, Robert
中科院分区：
文献类型：
--
作者：
Gomez, Bianca P.;Riggins, Rebecca B.;Clarke, Robert
人 X-box 结合蛋白-1 (XBP1) 是一种选择性剪接转录因子，参与未折叠蛋白反应 (UPR)，这是一种应激信号通路，使细胞能够在内质网腔中未折叠蛋白的积累中存活下来。我们之前已经证明，XBP1 表达在抗雌激素耐药的乳腺癌细胞系中增加，并且在乳腺肿瘤中与雌激素受体 α (ER) 共表达。本研究的目的是探讨 XBP1 和 UPR 在乳腺癌雌激素和抗雌激素反应中的作用。 ER 阳性乳腺癌细胞中剪接的 XBP1 [XBP1(S)] 的过度表达导致不依赖于雌激素的生长，并以不依赖于功能性 p53 的方式降低对抗雌激素他莫昔芬和 Faslodex 诱导的生长抑制的敏感性。基因表达微阵列分析的数据表明，XBP1(S) 通过调节 ER、抗凋亡基因 BCL2 以及其他几个与细胞周期和凋亡控制相关的基因的表达来发挥作用。检验这一假设，我们发现 XBP1(S) 的过度表达可通过线粒体凋亡途径阻止细胞周期停滞和抗雌激素诱导的细胞死亡。 XBP1 和/或 UPR 可能是开发乳腺癌新型预测和治疗策略的有用分子靶点。 -Gomez, B. P.、Riggins, R. B.、Shajahan, A.、Klimach, U.、Wang, A.、Crawford, A. C.、Zhu, Y.、Zwart, A.、Wang, M.、Clarke, R。人 X-Box 结合蛋白-1 赋予乳腺癌细胞系雌激素独立性和抗雌激素抵抗性。
Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress-signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. We have previously demonstrated that XBP1 expression is increased in antiestrogen-resistant breast cancer cell lines and is coexpressed with estrogen receptor alpha (ER) in breast tumors. The purpose of this study is to investigate the role of XBP1 and the UPR in estrogen and antiestrogen responsiveness in breast cancer. Overexpression of spliced XBP1 [XBP1(S)] in ER-positive breast cancer cells leads to estrogen-independent growth and reduced sensitivity to growth inhibition induced by the antiestrogens Tamoxifen and Faslodex in a manner independent of functional p53. Data from gene expression microarray analyses imply that XBP1(S) acts through regulation of the expression of ER, the antiapoptotic gene BCL2, and several other genes associated with control of the cell cycle and apoptosis. Testing this hypothesis, we show that overexpression of XBP1(S) prevents cell cycle arrest and antiestrogen-induced cell death through the mitochondrial apoptotic pathway. XBP1 and/or the UPR may be a useful molecular target for the development of novel predictive and therapeutic strategies in breast cancer. -Gomez, B. P., Riggins, R. B., Shajahan, A., Klimach, U., Wang, A., Crawford, A. C., Zhu, Y., Zwart, A., Wang, M., Clarke, R. Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines.