Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines

Bianca P. Gomez, Rebecca B. Riggins, Ayesha N. Shajahan, Uwe Klimach, Aifen Wang, Anatasha C. Crawford, Yuelin Zhu, Alan Zwart, Mingyue Wang, Robert Clarke

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4013-4027
Number of pages15
JournalFASEB Journal
Volume21
Issue number14
DOIs
StatePublished - Dec 2007
Externally publishedYes

Keywords

  • Apoptosis
  • Aromatase
  • Cell cycle
  • Faslodex
  • Proliferation
  • SERD
  • SERM
  • Tamoxifen
  • Unfolded protein response
  • XBPI

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