STAT3 Targets ERR-α to Promote Epithelial-Mesenchymal Transition, Migration, and Invasion in Triple-Negative Breast Cancer Cells

STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor a (ERR-alpha) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-alpha promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-alpha, and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation assay. We also found that ERR-alpha was the key target gene regulated by STAT3 in promoting epithelial-mesenchymal transition (EMT), migration, and invasion. ERR-alpha upregulated the expression of ZEB1, N-cadherin, and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-alpha could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-alpha was a direct regulatory gene target of p-STAT3, which was enriched for processes involving invasion and metastasis in TNBC and provided insight into TNBC pathogenesis, as well as a potential therapeutic option against TNBC metastasis.