stf-083010 and Breast-Neoplasms

Recent studies show that the unfolded protein response (UPR) within the endoplasmic reticulum is correlated with breast cancer drug resistance. In particular, human X-box binding protein-1(XBP1), a transcription factor which participates in UPR stress signaling, is reported to correlate with poor clinical responsiveness to tamoxifen. In this study, we develop a tamoxifen-resistant MCF-7 cell line by treating the cell line with low concentration of tamoxifen, and we find that XBP1 is indeed up-regulated at both the mRNA and protein levels compared to normal MCF-7 cells. STF-083010, a novel inhibitor which specifically blocks the XBP1 splicing, reestablishes tamoxifen sensitivity to resistant MCF-7 cells. Moreover, co-treatment with STF-083010 and tamoxifen can significantly delay breast cancer progression in a xenograft mammary tumor model. We next investigate the expression of XBP1s in over 170 breast cancer patients' samples and the results demonstrate that XBP1s expression level is highly correlated with overall survival in the ER+ subgroup, but not in the ER- subgroup, suggesting a potential therapeutic application of XBP1 inhibitors in ER+breast cancer treatment.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Proliferation; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endoribonucleases; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prognosis; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sulfonamides; Survival Rate; Tamoxifen; Thiophenes; Transcription Factors; Tumor Cells, Cultured; Unfolded Protein Response; X-Box Binding Protein 1; Xenograft Model Antitumor Assays