Nuclear orphan receptor ERRα promotes cisplatin resistance in breast cancer cells by targeting CCNE2

Abstract Background Chemotherapy is one of the most efficient therapeutic methods for cancer, but increasingly serious drug resistance is the main cause of cancer recurrence and treatment failure. Our study aimed to investigate the mechanisms by which upregulation of estrogen-related receptor α (ERRα) induced chemoresistance in breast cancer cells. Methods Immunohistochemistry (IHC) was used to determine the expression of ERRα in breast cancer and adjacent tissues. Functional analyses (in vitro and in vivo) were performed to confirm the role of ERRα in cancerogenesis and cisplatin chemoresistance in breast cancer. RNA-sequencing, ChIP-seq and dual luciferase assays were performed to identify the mechanisms by which ERRα promotes chemoresistance in breast cancer. Results ERRα was highly expressed in breast cancer tissues and the level of ERRα expression was determined to be significantly correlated with the expression level of human epidermal growth factor receptor 2 (HER2). Overexpression of ERRα promoted the proliferation and metastasis of breast cancer in vitro and in vivo while knockdown of ERRα suppressed. Moreover, ERRα was upregulated in chemoresistant breast cancer cells, while ERRα knockdown sensitized cisplatin treatment. Our results further demonstrated that ERRα enhanced the pluripotency of cancer cells and facilitated chemoresistance via upregulating CCNE2 by binding its promoter region. Overexpression of CCNE2 could reverse the sensitivity of breast cancer cells to cisplatin caused by ERRα depletion, thus resulting in accelerated tumor growth. Conclusion We identify that ERRα sustains the chemoresistance of breast cancer cells via regulating the transcription of CCNE2 and may serve as a therapeutic target in breast cancer.