REG gamma is a proteasome coactivator which regulates proteolytic activity in eukaryotic cells. Abundant lines of evidence have showed that REG gamma is over expressed in a number of human carcinomas. However, its precise role in the pathogenesis of cancer is still unclear. In this study, by examining 200 human breast cancer specimens, we demonstrated that REG gamma was highly expressed in breast cancers, and the expression of REG gamma was positively correlated with breast cancer patient estrogen receptor alpha (ER alpha) status. Moreover, the expression of REG gamma was found positively associated with poor clinical features and low survival rates in Elbx positive breast cancer patients. Further cell culture studies using MCF7 and BT474 breast cancer cell lines showed that cell proliferation, motility, and invasion capacities were decreased significantly by REG gamma knockdown. Lastly, we demonstrated that REG gamma indirectly regulates the degradation of ER alpha protein via ubiquitin proteasome pathway. In conclusion, our findings provide the evidence that REG gamma expression was positively correlated with ER alpha status and poor clinical prognosis in ER alpha positive breast cancer patients. As well, we disclose a new connection between the two molecules that are both highly expressed in most breast cancer cases. (C) 2014 Elsevier Inc. All rights reserved.