BACKGROUND: Breast cancer (BC) is highly heterogeneous with ~ 60-70% of estrogen receptor positive BC patient's response to anti-hormone therapy. Estrogen receptors (ERs) play an important role in breast cancer progression and treatment. Estrogen related receptors (ERRs) are a group of nuclear receptors which belong to orphan nuclear receptors, which have sequence homology with ERs and share target genes. Here, we investigated the possible role and clinicopathological importance of ERRbeta in breast cancer. METHODS: Estrogen related receptor beta (ERRbeta) expression was examined using tissue microarray slides (TMA) of Breast Carcinoma patients with adjacent normal by immunohistochemistry and in breast cancer cell lines. In order to investigate whether ERRbeta is a direct target of ERalpha, we investigated the expression of ERRbeta in short hairpin ribonucleic acid knockdown of ERalpha breast cancer cells by western blot, qRT-PCR and RT-PCR. We further confirmed the binding of ERalpha by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), Re-ChIP and luciferase assays. Fluorescence-activated cell sorting analysis (FACS) was performed to elucidate the role of ERRbeta in cell cycle regulation. A Kaplan-Meier Survival analysis of GEO dataset was performed to correlate the expression of ERRbeta with survival in breast cancer patients. RESULTS: Tissue microarray (TMA) analysis showed that ERRbeta is significantly down-regulated in breast carcinoma tissue samples compared to adjacent normal. ER + ve breast tumors and cell lines showed a significant expression of ERRbeta compared to ER-ve tumors and cell lines. Estrogen treatment significantly induced the expression of ERRbeta and it was ERalpha dependent. Mechanistic analyses indicate that ERalpha directly targets ERRbeta through estrogen response element and ERRbeta also mediates cell cycle regulation through p18, p21(cip) and cyclin D1 in breast cancer cells. Our results also showed the up-regulation of ERRbeta promoter activity in ectopically co-expressed ERalpha and ERRbeta breast cancer cell lines. Fluorescence-activated cell sorting analysis (FACS) showed increased G0/G1 phase cell population in ERRbeta overexpressed MCF7 cells. Furthermore, ERRbeta expression was inversely correlated with overall survival in breast cancer. Collectively our results suggest cell cycle and tumor suppressor role of ERRbeta in breast cancer cells which provide a potential avenue to target ERRbeta signaling pathway in breast cancer. CONCLUSION: Our results indicate that ERRbeta is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. ERRbeta could be therapeutic target for the treatment of breast cancer.