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

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.

Autophagy Induced by Deficiency of Sphingosine-1-phosphate Phosphohydrolase 1 Is Switched to Apoptosis by Calpain-mediated Autophagy-related Gene 5 (Atg5) Cleavage

“…Moreover, SPP1 levels change in response to some stimuli that alter the UPR. Analysis of MCF7 breast cancer cells overexpressing XBP-1, a transcription factor that participates in the UPR and confers both estrogen independence and anti-estrogen resistance, revealed that SPP1 was among the genes that were significantly up-regulated (36). In agreement, we found that doxorubicin, similar to other stimuli that alter the UPR, up-regulates SPP1.…”

Activation and clinical significance of the unfolded protein response in breast cancer

“…There is speculation that activation of the UPR may be associated with the development of anti-oestrogen resistance (Fu et al, 2007;Gomez et al, 2007). UPR induction reduces the occurrence of apoptosis in oestrogen-dependent breast cancer cells treated by oestrogen withdrawal, (which clinically correlates with the use of aromatase inhibitors, Fu et al, 2007).…”

“…Over-expression of XBP-1, another marker of UPR activity, is correlated with resistance to the apoptotic and anti-proliferative effects of antioestrogens, (Davies et al, 2008). The UPR-activated splice variant of XBP-1, (XBP-1s), confers anti-oestrogen resistance and oestrogen-independent growth in breast cancer cell lines in vitro (Gomez et al, 2007).…”

“…The UPR also interacts with oestrogen responsive pathways in breast cancer and has recently been proposed to contribute to the development of anti-oestrogen resistance (Fu et al, 2007;Gomez et al, 2007;Davies et al, 2008).…”

Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma

“…Recently, it was reported that XBP1s overexpression leads to increased BCL-2 expression in a breast cancer cell line (19). In a hematopoietic cell line that undergoes apoptosis upon interleukin (IL)-3 withdrawal, overexpression of XBP1s was cytoprotective and attenuated induction of the proapoptotic BCL-2 family member BIM (20).…”