Human X-box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines.
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.
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Rd., NW, Washington, DC 20057, USA.
Bianca P
BP
Gomez
Rebecca B
RB
Riggins
Ayesha N
AN
Shajahan
Uwe
U
Klimach
Aifen
A
Wang
Anatasha C
AC
Crawford
Yuelin
Y
Zhu
Alan
A
Zwart
Mingyue
M
Wang
Robert
R
Clarke
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D004967:Estrogens / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012326:RNA Splicing / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006131:Growth Inhibitors; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human