Estrogen related receptor beta (ERRβ) is down-regulated in breast cancer cells and its over expression in breast cancer patients is positively correlated with an improved prognosis and prolonged relapse-free survival. Here, we unravelled a molecular mechanism for ERRβ down-regulation in breast cancer. We found that ERRβ is a key substrate of the SCF complex and that NEDDylation can activate the Cullin sub units of the SCF complex to target ERRβfor degradation in breast cancer. Consistently, using in vitro and in vivo models, we demonstrated that MLN4924, a specific small molecule inhibitor of NEDDylation, can restore ERRβ expressionand culminate in a reduction in cell proliferation and migration of breast cancer cells.We also showed that increased ERRβ expression promotes the up-regulation of its 34target genes, including the tumour suppressors p21Cip1/Waf1and E-cadherin,involved in cell proliferation and migration arrest at the gene promoter level. Interestingly, this tumour suppressive role of ERRβ does not depend on the expression of ERain breast cancer. Moreover, our data revealed that the ERRβ recruits the transcription co-activator p300 to its targeted gene promoters to up regulate their expression. Collectively,our work revealed that restoration of ERRβ expression using the NEDDylation inhibitor MLN4924 can be a novel and effective strategy for breast cancer treatment