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

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many malignant tumour types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in TNBC cell lines and tissues, which was associated with both the pathological stage and prognosis of TNBC patients. In vitro studies showed that ERR-α promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-α and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation (Ch-IP) assay. We also found that ERR-α was the key target gene regulated by STAT3 in promoting epithelial-mesenchymal transition (EMT), migration and invasion. ERR-α upregulated the expression of ZEB1, N-cadherin and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-α could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-α 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. Implications: Our research first showed that phosphorylated STAT3 (Tyr 705) could bind to the promotor region of estrogen related receptor-α and promote EMT in TNBC by ZEB1 pathways, thus provided a potential clinical target of TNBC.