Oncotarget

Research Papers:

A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1

Jie Ming _, Shengnan Ruan, Mengyi Wang, Dan Ye, Ningning Fan, Qingyu Meng, Bo Tian and Tao Huang

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Oncotarget. 2015; 6:40692-40703. https://doi.org/10.18632/oncotarget.5827

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Abstract

Jie Ming1,*, Shengnan Ruan1,*, Mengyi Wang1, Dan Ye1, Ningning Fan2, Qingyu Meng3, Bo Tian4,5, Tao Huang1

1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China

2Department of Breast and Thyroid Surgery, Luoyang Central Hospital, Zhengzhou University, Luoyang, Henan 471009, P.R. China

3Department of Radiation Oncology, Peking Union Medical College hospital, Beijing 100730, P.R. China

4Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China

5Key Laboratory of Neurological Diseases of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Jie Ming, e-mail: mingjiewh@126.com

Tao Huang, e-mail: huangtaowh@163.com

Keywords: STF-080310, tamoxifen, breast cancer, IRE1/XBP1

Received: May 21, 2015     Accepted: September 23, 2015     Published: October 19, 2015

ABSTRACT

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.


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