Gomez Bianca P, Riggins Rebecca B, Shajahan Ayesha N, Klimach Uwe, Wang Aifen, Crawford Anatasha C, Zhu Yuelin, Zwart Alan, Wang Mingyue, Clarke Robert
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Rd., NW, Washington, DC 20057, USA.
FASEB J. 2007 Dec;21(14):4013-27. doi: 10.1096/fj.06-7990com. Epub 2007 Jul 27.
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.
人类X盒结合蛋白1（XBP1）是一种可变剪接的转录因子，参与未折叠蛋白反应（UPR），这是一种应激信号通路，可使细胞在内质网腔中未折叠蛋白积累的情况下存活。我们之前已经证明，XBP1在抗雌激素耐药的乳腺癌细胞系中表达增加，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性中的作用。在雌激素受体阳性的乳腺癌细胞中过表达剪接型XBP1 [XBP1(S)]会导致雌激素非依赖性生长，并以独立于功能性p53的方式降低对抗雌激素他莫昔芬和氟维司群诱导的生长抑制的敏感性。基因表达微阵列分析数据表明，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基因的表达来发挥作用。通过验证这一假设，我们发现XBP1(S)的过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。
