Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin
Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin
Triple-negative breast cancer (TNBC) patients have poor prognosis due to the aggressive metastatic behaviors. Our study reveals that expression of estrogen related receptor α (ERRα) is significantly (p < 0.01) positively associated with high grade tumors and lymph node metastasis, while negatively correlated with overall survival (OS), in 138 TNBC patients. Targeted inhibition of ERRα by its inverse agonist XCT-790 or si-RNA obviously inhibits in vitro motility of TNBC cells. While over expression of ERRα triggers the invasion and migration of TNBC cells. Further, si-ERRα and XCT-790 inhibit the epithelial mesenchymal transition (EMT) of TNBC cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. While XCT-790 has no effect on the expression of EMT related transcription factors such as Snail or Slug. Further, inhibitors of MAPK, PI3K/Akt, NF-κB signal molecules, which are activated by XCT-790, can not attenuate the suppression effects of XCT-790 on EMT. Alternatively, luciferase reporter gene assays and ChIP analysis indicate that ERRα can directly bind with FN promoter at ERR response element-3 (ERRE-1), ERRE-3, and ERRE-4, while XCT-790 reduces this bond. In vivo data show that ERRα expression is significantly (p < 0.05) correlated with FN in clinical TNBC patients. In MDA-MB-231 tumor xenograft models, XCT-790 decreases the expression of FN, inhibits the growth and lung metastasis, and suppresses the EMT. Our results demonstrate that ERRα functions as a metastasis stimulator and its targeted inhibition may be a new therapeutic strategy for TNBC treatment.
- Sun Yat-sen University Cancer Center China (People's Republic of)
- Peking University Cancer Hospital China (People's Republic of)
- State Key Laboratory of Oncology in South China China (People's Republic of)
- Guangzhou Medical University China (People's Republic of)
- Sun Yat-sen University China (People's Republic of)
Binding Sites, Epithelial-Mesenchymal Transition, Lung Neoplasms, Dose-Response Relationship, Drug, Drug Inverse Agonism, Mice, Nude, Antineoplastic Agents, Hep G2 Cells, Middle Aged, Fibronectins, Gene Expression Regulation, Neoplastic, Cell Movement, Nitriles, MCF-7 Cells, Animals, Humans, Female, RNA Interference, Promoter Regions, Genetic, Protein Binding
Binding Sites, Epithelial-Mesenchymal Transition, Lung Neoplasms, Dose-Response Relationship, Drug, Drug Inverse Agonism, Mice, Nude, Antineoplastic Agents, Hep G2 Cells, Middle Aged, Fibronectins, Gene Expression Regulation, Neoplastic, Cell Movement, Nitriles, MCF-7 Cells, Animals, Humans, Female, RNA Interference, Promoter Regions, Genetic, Protein Binding
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