科研之友
微信
新浪微博
Facebook
分享链接
摘要
Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-alpha level is considered a primary mechanism. Understanding how ER-alpha expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of delta EF1 is up-regulated by 17 beta-estradiol (E2) in MCF-7 cells in an ER-alpha-dependent manner, through either PI3K or NF-kappa B pathway. Ectopic expression of delta EF1 in turn repressed ER-alpha transcription by binding to the E-2-box on the ER-alpha promoter. At the tissue level of breast cancer, there is a strong and inverse correlation between the expression levels of delta EF1 and ER-alpha. In MCF-7 cells, an elevated expression of delta EF1 made the cells less sensitive to tamoxifen treatment, whereas overexpression of ER-alpha compromised the effects of delta EF1 and restored the sensitivity. Also, depletion of delta EF1 by RNA interference in MDA-MB-231 cells restored the expression of ER-alpha and tamoxifen sensitivity. In conclusion, we have identified an important role of delta EF1 in the development of tamoxifen resistance in breast cancer. Inhibiting delta EF1 to restore ER-alpha expression might represent a potential therapeutic strategy for overcoming endocrine resistance in breast cancer.
