EF1 Down-Regulates ER-[alpha] Expression and Confers Tamoxifen Resistance in Breast Cancer

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.sub.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.