表柔比星作为治疗乳腺癌最有效的化学治疗药物之一,但继发性耐药的产生严重制约了该药物在临床上的应用。我们在继发性耐药的乳腺癌细胞中发现,硒结合蛋白SBP1参与了表柔比星耐药机制的产生。进一步研究,发现了SBP1新的生物学功能,即SBP1对在谷胱甘肽合成限速环节起关键作用的胱氨酸/谷氨酸反向转运体亚基xCT的mRNA和蛋白存在调控作用,提示SBP1抑制xCT转录。此外,我们发现SBP1特异性地抑制转录因子STAT1的磷酸化,而STAT1对xCT存在正向调控作用;而且发现xCT启动子上存在STAT1的潜在结合位点。因此,本项目拟采用基因干扰、启动子定点突变和ChIP等实验技术,旨在回答SBP1如何通过STAT1直接转录调控xCT这一关键科学问题。本项目的实施将阐明SBP1/STAT1/xCT通路对表柔比星药物敏感性的影响,为确立SBP1作为逆转乳腺癌表柔比星耐药的新靶点提供科学依据。

Although epirubicin (EPI) is one of the most effective drugs against breast cancer, the acquired resistance of breast cancer cells to EPI is becoming a major obstacle for successful therapy. In the established EPI-resistant breast cancer cells, we found Selenium Binding Protein 1 (SBP1) was indeed involved in the development of acquired resistance of breast cancer cells to EPI. Furthermore, we identified a novel function for SBP1 in the regulation of the mRNA and protein expression of xCT, a light subunit conferring transport and substrate specificity of Xc- cystine/glutamate antiporter which plays a rate-limiting role in the biosynthesis of glutathione. In addition, we revealed that SBP1 repressed the phosphorylation levels of transcription factor STAT1, while STAT1 positively regulated xCT protein expression. Bioinformatics analysis indicated that there are several potential binding site of STAT1 in xCT promote. Collectively, these findings led us to the hypothesis that SBP1 inhibits the transcription of xCT via STAT1. Therefore, this project aims to investigate the molecular mechanism underlying STAT1-mediated transcription regulation of xCT by SBP1 in breast cancer, finally verifying the potential role for SBP1/STAT1/xCT signaling in restoring the sensitivity of breast cancer to EPI. These findings will provide mechanistic insights and identify novel therapeutic targets for cracking the hard nuts of the acquired resistance of breast cancer to EPI.