?EF1 down-regulates ER-? expression and confers tamoxifen resistance in breast cancer.

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

SUBMITTER: Guo S 

PROVIDER: S-EPMC3528679 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature