The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer

Du, Yipeng; Song, Lianhua; Zhang, Liudi; Hao, Ling; Zhang, Yanhui; Chen, Haifei; Qi, Huijie; Shi, Xiaojin; Li, Qunyi

doi:10.1016/j.ejmech.2017.04.050

Cited by 25 publications

(21 citation statements)

References 20 publications

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“… 14 XCT790 is thought to downregulate the expression of the ERRα gene by inducing an actively repressive conformation. 32 We found that XCT790 inhibited the expression of ERRα not only in the ERα-negative and/or ERα-nonresponsive EC cells HEC-1A and HEC-1B, but also in the ERα-positive and -responsive EC cell lines RL-952 and AN3-CA. XCT790 treatment resulted in the inhibition of cellular proliferation via ERRα downregulation in all four cell lines.…”

Section: Discussionmentioning

confidence: 73%

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA

Sun¹,

Mao²,

Gao³

et al. 2018

CMAR

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PurposeTo explore the targeted therapy of estrogen-related receptor α (ERRα) in endometrial cancer (EC) cells and its potential mechanisms.MethodsThe mRNA and protein expression levels of ERRα and estrogen receptor α (ERα) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERRα-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERRα (siRNA-ERRα), cell proliferation and apoptosis were evaluated by MTS assay and flow cytometry. After treatment with siRNA-ERRα, the expression profiles of transcription factors (TFs) were analyzed by protein/DNA arrays in EC cells.ResultsThe relative mRNA levels of ERRa in RL-952 (1±0.0831) and AN3-CA (1.162±0.0325) were significantly higher than those in HEC-1A (0.3081±0.0339) and HEC-1B (0.1119±0.0091) (P<0.05), and similar results were observed for ERRα protein levels. A higher ratio of ERa/ERRa was observed in ERα-positive RL-952 (10-fold) and ANC-3A (8.5-fold) cells, whereas a lower ratio was observed in ERα-negative HEC-1A (3.75-fold) and HEC-1B cells (0-fold). Both – exogenous XCT790 and endogenous siRNA-ERRα – can decrease the expression of ERRα, thereby inhibiting proliferation but promoting apoptosis in both ERα-positive and -negative EC cells. The XCT790 presented higher proliferation-inhibition and apoptosis rates in the ERα-positive than ERα-negative cells, whereas the siRNA-ERRα exhibited higher proliferation-inhibition and apoptosis rates in the ERα-negative than in ERα-positive cells. In total, 3 upregulated and 17 downregulated TFs were screened out by knocked-down expression of ERRα in all EC cells. Among them, the upregulated TFs organic cation transporter 3/4(Oct3/4), hepatic nuclear factor 4 (HNF4), HNF4 and chicken ovalbumin upstream TF (COUP-TF) as well as downregulated transcription factor EB (TFEB) were found to be statistically significant (P<0.05).ConclusionTargeting ERRα provides a promising novel endocrine therapeutic strategy.

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Section: Discussionmentioning

confidence: 73%

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA

Sun¹,

Mao²,

Gao³

et al. 2018

CMAR

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“…A synthetic ERRα ligand named compound 11 potently inhibited ERRα's transcriptional activity and inhibited the migration of TNBC breast cancer cells. In vivo, compound 11 demonstrated a strong inhibitory effect on the growth of TNBC xenografts (MDA-MB-231), reducing the tumor growth by 40.9% [87]. Although the exact role of GPER-1 in TNBC is still controversial, activation of this receptor by its specific agonist G-1 was reported to exert antitumoral effects on TNBC cells.…”

Section: Endocrine Therapy Of Tnbc Targeting Estrogen Signalingmentioning

confidence: 99%

Estrogen Actions in Triple-Negative Breast Cancer

Treeck¹,

Schüler-Toprak²,

Ortmann³

2020

Cells

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Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is able to trigger estrogen-responsivity in TNBC. Estrogen signaling in TNBC can also be activated and modulated by the constitutively active estrogen-related receptors (ERRs). In this review article, we discuss the role of ERβ and GPER-1 as mediators of E2 action in TNBC as well as the function of ERRs as activators and modulators of estrogen signaling in this cancer entity. For this purpose, original research articles on estrogen actions in TNBC were considered, which are listed in the PubMed database. Additionally, we performed meta-analyses of publicly accessible integrated gene expression and survival data to elucidate the association of ERβ, GPER-1, and ERR expression levels in TNBC with survival. Finally, options for endocrine therapy strategies for TNBC were discussed.

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“…To further explore the role of ERRα in MDA-MB-231 cells we used its well recognized inverse agonist XCT-790 14,15,17 and analyzed protein expression and promoter activity of the ACSL4 gene. Incubation with XCT-790 produced inhibition in ACSL4 levels analyzed by Western blot and also in promoter activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells

Dattilo

Benzo

Herrera

et al. 2019

Sci Rep

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Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer. In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. However, the upstream regulatory mechanisms leading to differential ACSL4 expression between triple negative breast cancer and ERα-positive cells remained unknown. We performed the characterization of the human ACSL4 promoter and the identification of transcription factors involved. Deletional analysis demonstrated the proximal 43 base pairs of the promoter are involved in overexpression. By site directed mutagenesis we describe that retinoid-related orphan receptor alpha (RORα), Sp1 and E2F elements are involved in the promoter activity. We established for the first time that estrogen-related receptor alpha (ERRα) is a transcription factor involved in the higher activation of the human ACSL4 promoter in breast cancer cells. Furthermore, a combination of inhibitors of ACSL4 and ERRα produced a synergistic decrease in MDA-MB-231 cell proliferation. We also demonstrated that ERα restoration in triple negative breast cancer cells downregulates ACSL4 expression. The results presented in this manuscript demonstrated transcriptional mechanism is involved in the different expression of ACSL4 in human breast cancer cell lines of different aggressiveness.

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The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer

Cited by 25 publications

References 20 publications

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA

Estrogen Actions in Triple-Negative Breast Cancer

Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells

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The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer

Cited by 25 publications

References 20 publications

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor &alpha; by XCT790 and siRNA

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor &alpha; by XCT790 and siRNA

Estrogen Actions in Triple-Negative Breast Cancer

Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells

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Product

Resources

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Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA