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Human X‐Box binding protein‐1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines
Author(s) -
Gomez Bianca P.,
Riggins Rebecca B.,
Shajahan Ayesha N.,
Klimach Uwe,
Wang Aifen,
Crawford Anatasha C.,
Zhu Yuelin,
Zwart Alan,
Wang Mingyue,
Clarke Robert
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7990com
Subject(s) - xbp1 , antiestrogen , unfolded protein response , estrogen receptor , tamoxifen , biology , cancer research , estrogen receptor alpha , transcription factor , breast cancer , endoplasmic reticulum , microbiology and biotechnology , cancer , gene , genetics , rna , rna splicing
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 anti‐apoptotic 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 resis‐tance in breast cancer cell lines. FASEB J . 21, 4013–4027 (2007)