Triple-negative Breast Cancer: Identification of circRNAs With Efficacy in Preclinical<i>In Vivo</i>Models

Weidle, Ulrich H.; Birzele, Fabian

doi:10.21873/cgp.20368

Cited by 9 publications

(10 citation statements)

References 164 publications

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“…Therefore, acquired resistance to paclitaxel is undoubtedly the biggest obstacle in improving the overall response and survival of patients with TNBC. In recent years, owing to the stability and abundance of circRNAs, an increasing number of circRNAs have been identi ed as abnormally expressed in TNBC; as important regulators of TNBC cancer progression, circRNAs are of great signi cance for the resistance of TNBC [9,19]. However, research on circRNAs associated with paclitaxel resistance in TNBC remains limited.…”

Section: Discussionmentioning

confidence: 99%

“…These advantages, compared to lncRNAs and miRNAs, have the potential to be ideal biomarkers for the treatment of cancer diseases [8]. Many studies have demonstrated that abnormal expression of circRNAs is inextricably linked to tumorigenesis and chemical resistance in TNBC [9,10]. For example, Zheng et al reported that CircGFRA1 affects the sensitivity of TNBC cells to paclitaxel [10].…”

Section: Introductionmentioning

confidence: 99%

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CircRNA_0044556 regulates paclitaxel resistance in triple-negative breast cancer by targeting miR-665

chen,

shi,

cui

et al. 2023

Preprint

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Background CircRNAs have been significantly implicated in the development and resistance of triple-negative breast cancer (TNBC). However, the association between circRNA_0044556 and TNBC paclitaxel (PTX) resistance is still limited. Therefore, the purpose of this study was to investigate the effect of circRNA_0044556 on the biological function and PTX resistance of TNBC cells. Methods PTX-resistant TNBC cells (MDA-MB-231/PTX) were obtained by continuously exposing MDA-MB-231 cells to increased paclitaxel levels. First, the expression levels of circRNA_0044556 and miR-665 were measured by qRT‒PCR. Then, the regulatory relationship between miR-665 and circRNA_0044556 was verified by biological information website analysis and double luciferase reporter gene detection experiments. Finally, MTT assay, clonogenesis assay, flow cytometry and Western blot analysis were used to evaluate the influence of cell biological function. Results Elevated circRNA_0044556 was present in TNBC, and paclitaxel increased the expression of circRNA_0044556 in TNBC cells. In TNBC, circRNA_0044556 acts as a ceRNA for miR-665. In addition, low expression of circRNA_0044556 combined with miR-665 inhibited the proliferation of TNBC cells and paclitaxel-resistant TNBC cells while inducing cell death. Conclusions Our study demonstrated that downregulation of circRNA_0044556 inhibited the malignant progression of TNBC cells and paclitaxel resistance via miR-665. Thus, circRNA_0044556 may be a potential therapeutic target for TNBC paclitaxel resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CircRNA_0044556 regulates paclitaxel resistance in triple-negative breast cancer by targeting miR-665

chen,

shi,

cui

et al. 2023

Preprint

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“…It is well established that E3 ligases, including SYVN1 can have opposite effects as either tumor suppressors (TS) or oncogenes depending on the context or type of cancer ( 73 – 75 ). With regards to SYVN1, previous studies have shown that it functions as a tumor suppressor in breast ( 37 , 39 , 41 , 76 , 77 ) and ovarian ( 40 ) cancers.…”

Section: Discussionmentioning

confidence: 99%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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“…Triple-negative breast cancer (TNBC) [40] Circ-HER2 [41] Circ-TADA2A-E6 [42] Has-circ-0025202 Breast cancer (BC) [43] Circ-Dnmt1 [44] Circβ-catenin Hepatocellular carcinoma (HCC) [45] Circ-RNA-104718 [46] Circ-TRIM33-12 [47] Circ-RNA 100146 Non-small cell lung cancer (NSCLC) [48] Circ-PTPRA [49] Table 2. Cont.…”

Section: Circ-agfg1mentioning

confidence: 99%

Smart Nanocarriers for the Targeted Delivery of Therapeutic Nucleic Acid for Cancer Immunotherapy

et al. 2023

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A wide variety of therapeutic approaches and technologies for delivering therapeutic agents have been investigated for treating cancer. Recently, immunotherapy has achieved success in cancer treatment. Successful clinical results of immunotherapeutic approaches for cancer treatment were led by antibodies targeting immune checkpoints, and many have advanced through clinical trials and obtained FDA approval. A major opportunity remains for the development of nucleic acid technology for cancer immunotherapy in the form of cancer vaccines, adoptive T-cell therapies, and gene regulation. However, these therapeutic approaches face many challenges related to their delivery to target cells, including their in vivo decay, the limited uptake by target cells, the requirements for nuclear penetration (in some cases), and the damage caused to healthy cells. These barriers can be avoided and resolved by utilizing advanced smart nanocarriers (e.g., lipids, polymers, spherical nucleic acids, metallic nanoparticles) that enable the efficient and selective delivery of nucleic acids to the target cells and/or tissues. Here, we review studies that have developed nanoparticle-mediated cancer immunotherapy as a technology for cancer patients. Moreover, we also investigate the crosstalk between the function of nucleic acid therapeutics in cancer immunotherapy, and we discuss how nanoparticles can be functionalized and designed to target the delivery and thus improve the efficacy, toxicity, and stability of these therapeutics.

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Triple-negative Breast Cancer: Identification of circRNAs With Efficacy in PreclinicalIn VivoModels

Abstract: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0

Cited by 9 publications

References 164 publications

CircRNA_0044556 regulates paclitaxel resistance in triple-negative breast cancer by targeting miR-665

CircRNA_0044556 regulates paclitaxel resistance in triple-negative breast cancer by targeting miR-665

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Smart Nanocarriers for the Targeted Delivery of Therapeutic Nucleic Acid for Cancer Immunotherapy

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