ERRα confers oncogenesis and cisplatin resistance via transcriptionally activating CCNE2 in breast cancer

Abstract Background: Platinum is widely used in the neoadjuvant and metastatic treatment of breast cancer, but increasingly 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. 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 and dual luciferaseassays were performed to identify the mechanisms by which ERRα promotes chemoresistance in breast cancer. Results: Analyses of ERRα expression among a case-control cohort of 63 annotated tumor specimens demonstrated that ERRα expression was highly expressed in breast cancer tissues. Overexpression of ERRα promoted cell proliferation and metastasis of breast cancer in vitro and in vivo, increased chemoresistant of cisplatin and enhanced the pluripotency; while ERRα knockdown resulted in the opposite effects. We show that ERRα can directly induce CCNE2 expression through binding its promoter region then enhanced the pluripotency of cancer cells and facilitated chemoresistance Overexpression of CCNE2 could reverse the sensitivity of breast cancer cells to cisplatin caused by ERRα depletion, thus resulting in accelerated tumor growth. Conclusions: Our study demonstrates that ERRα acts as oncogene in breast cancer and promotes cisplatin resistance by regulating the transcription of CCNE2 and may serve as a therapeutic target in breast cancer.