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.
Highlights
Tamoxifen (TAM) is one of the most frequently used, and effective, endocrine treatment drugs, which can reduce mortality and breast cancer recurrence in patients with hormone receptor positive breast tumors
Microscopic analysis was used to assess the morphological changes upon tamoxifen treatment; we found that control MCF-7 cells displayed a highly round morphology, while the MCF7-TAMR cells showed more branches and displayed a long, flat morphology which were similar to normal tissue epithelia (Figure 1b)
To compare X-box binding protein-1 (XBP1) expression level between control cells and tamoxifen resistant cells, we performed RTPCR to analyze the mRNA level of XBP1s and XBP1u, and the XBP1s/ XBP1u ratio was used as a measure of XBP1 splicing activity
Summary
Tamoxifen (TAM) is one of the most frequently used, and effective, endocrine treatment drugs, which can reduce mortality and breast cancer recurrence in patients with hormone receptor positive breast tumors. Up to 50% of estrogen or progesterone receptor positive breast cancers do not respond to endocrine therapies, displaying de novo or intrinsic resistance. The development of novel and efficient therapies for tamoxifen-resistant breast cancer remains a major challenge for breast cancer researchers and clinicians. [1] The unfolded protein response (UPR), a collective set of signaling pathways which is activated by endoplasmic reticulum (ER) stress, has been demonstrated to be one of the most important endocrine treatment-resistant mechanisms and represents a potential therapeutic target for tamoxifen-resistant breast cancer. XBP1s is more stable, easier to transport and a stronger transcriptional factor compared to its unspliced form, XBP1u. XBP1s is more stable, easier to transport and a stronger transcriptional factor compared to its unspliced form, XBP1u. [6]
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