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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.

Vesicle amine transport-1 (VAT-1) was implicated in regulation of vesicular transport, mitochondrial fusion, axonal growth, phospholipid transport and cell migration. However, the role of VAT-1 in tumour biology and disease progression of hepatocellular carcinoma (HCC) remains unknown. Here, we first investigated the expression of VAT-1 in clinical HCC samples by immunohistochemistry and in various transcriptomic datasets by bioinformatics. The biological functions of VAT-1 in HCC were then explored by using a variety of techniques including in vitro cell-based assays, in vivo xenograft models, high throughput mRNA-Seq, KEGG pathway enrichment, flow-cytometry analysis, immunoassays and bioinformatics. Underlying mechanisms were further verified in clinical tumour specimens. We demonstrated that VAT-1 is significantly upregulated in tumour tissues and associated with tumour size, invasion, clinical stage and overall survival of patients. Multivariate Cox analysis indicated VAT-1 is an independent unfavourable prognostic factor. VAT-1 downregulation significantly inhibited cell growth and colony formation in vitro and xenograft growth by decreasing proliferation and increasing apoptosis. Mechanistic studies revealed VAT-1 downregulation inhibits tumour growth through induction of the cell cycle arrest at G1-G0 by regulating the expression of cyclin D1, cyclin D3, CDK6, c-Myc and MCL-1. Strikingly, VAT-1 regulates STAT3 phosphorylation at Y705, nuclear translocation of pSTAT3-Y705, EGF-induced STAT3 signalling and consequently the expression of downstream c-Myc and cyclin D1. In both established HCC cell lines and clinical tumour samples, VAT-1 regulates numerous pathways including cell cycle, ErbB pathway, EGFR tyrosine kinase inhibitor resistance and JAK-STAT pathway; VAT-1 expression is significantly correlated with core components of EGF-EGFR-STAT3-cell cycle axis, highlighting the role of VAT-1 in regulation of EGF-STAT3-c-Myc-cyclin D/CDK6 signalling. Our results provide new insights into the carcinogenesis and disease progression of HCC and rationales for the development of novel intervention strategies against HCC. VAT-1 could serve as an independent prognostic biomarker for predicting clinical outcome of HCC patients.

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.