Estrogen-Estrogen Receptor alpha (ER alpha) belongs to one of the most important signaling pathways controlling breast tissue development and progression of breast cancer. ERRF was recently identified as a candidate breast cancer associated protein and showed positive association with ER alpha status in clinical samples and cell lines. To further explore the relationship between ERRF and ER alpha, we studied whether ERRF plays any roles in estrogen-ER alpha pathway. Knockdown of ERRF in ER positive breast cancer cells T-47D and BT-474 reduced the level of p-AKT, p-MAPK, and phosphorylation of ER alpha at Ser 118 and Ser 167, and the transcriptional activity of ER alpha was inhibited as well. Further mechanism study proved ERRF to be an interacting partner of ER alpha. In total, these data revealed that ERRF is essential for the activity of E2-ER alpha pathway. (C) 2016 Elsevier Inc. All rights reserved.