scholarly journals Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin Zheng ◽  
Zijian Liu ◽  
Mi Mi ◽  
Qiuyue Wen ◽  
Gang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Immune Checkpoint Blockade ◽  
Combination Group ◽  
Clinical Benefits ◽  
Programmed Death 1 ◽  
4T1 Breast Cancer

Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, disulfiram (DSF) kills tumor cells via regulating multiple signaling pathways and transcription factors. However, its effect on tumor immune microenvironment (TIME) remains unclear. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through bioinformatics analysis, we found that DNMT1 was highly expressed in TNBC tissue and PD-L1 was negatively correlated with IRF7 expression. DSF reduced DNMT1 expression and activity, and hypomethylated IRF7 promoter region resulting in upregulation of IRF7. Furthermore, we found DSF enhanced PD-L1 expression via DNMT1-mediated IRF7 hypomethylation. In in vivo experiments, DSF significantly improved the response to anti-PD-1 antibody (Ab) in 4T1 breast cancer mouse model. Immunohistochemistry staining showed that granzyme B+ and CD8+ T cells in the tumor tissues were significantly increased in the combination group. By analyzing the results of the tumor tissue RNA sequencing, four immune-associated pathways were significantly enriched in the DSF joint anti-PD-1 Ab group. In conclusion, we found that DSF could upregulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate TIME to show much better antitumor efficacy than monotherapy.

scholarly journals SphK2/S1P promotes metastasis in triple negative breast cancer through PAK1/LIMK1/Cofilin1 signaling pathway

2020 ◽  
Author(s):  
Weiwei Shi ◽  
Ding Ma ◽  
Yin Cao ◽  
Lili Hu ◽  
Shuwen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Specific Inhibitor ◽  
Downstream Signaling

Abstract Background: Triple negative breast cancer (TNBC) features poor prognosis which partialy attributed to the high metastasis rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, HER-2) up to date. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalysate sphingosine-1-phosphate (S1P) in TNBC metastasis, and the antitumor activity of SphK2 specific inhibitor ABC294640 in TNBC metastasis. Methods: The function of SphK2 and S1P in migration of TNBC cells was evaluated by Transwell migration and wound healing assays. The molecular mechanisms of SphK2/S1P mediating TNBC metastasis were investigated using cell line establishment, western blot, histological examination and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in TNBC lung metastasis model in vivo. Results: SphK2 regulated TNBC cells migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo . p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1) and Cofilin1 was the downstream signaling cascade of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P induced TNBC cells migration. Concusion: SphK2/S1P promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 potently inhibits TNBC metastasis in vivo which could be developed as a novel agent for the clinical treatment of TNBC.

scholarly journals The in vivo anti-tumor effect of curcumin derivative (2E,6E)-2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC) on 4T1 breast cancer cells

RSC Advances ◽  
2017 ◽  
Vol 7 (57) ◽  
pp. 36185-36192 ◽  
Author(s):  
Nursyamirah Abd Razak ◽  
M. Nadeem Akhtar ◽  
Nadiah Abu ◽  
Wan Yong Ho ◽  
Sheau Wei Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Antitumor Effect ◽  
Triple Negative ◽  
4T1 Breast Cancer ◽  
Curcumin Derivative

BHMC possessedin vitroandin vivoantitumor effect on 4T1 triple negative breast cancer cells.

scholarly journals Augmentation of Antitumour Function of Tumour-infiltrating Lymphocytes Against Triple-negative Breast Cancer by PD-1 Blockade

2021 ◽  
Author(s):  
Haiyan Hu ◽  
Hongming Song ◽  
Haibo Wang ◽  
Mingkai Gong ◽  
Li Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Adoptive Cell Therapy ◽  
Immune Checkpoint Blockade ◽  
In Vivo Model ◽  
Antitumour Effect

Abstract T-cell-based immunotherapy and immune checkpoint blockade have been successfully used to treat several human solid cancers. The present study attempted to investigate the feasibility and efficacy of the antitumour effect of adoptive cell therapy along with programmed cell death protein 1 (PD-1) inhibitor on triple-negative breast cancer (TNBC). We isolated and expanded tumour infiltration lymphocytes (TILs) from TNBC mouse tumour tissues and adoptive TIL transfusion (TILs-ACT) was applied in combination with a PD-1 inhibitor to the TNBC mouse model. The pre- and post-therapy antitumour efficacy, cytokine secretion, and pathological changes were assessed both in vitro and in vivo. TILs exhibited higher IFN-γ and TNF-α secretion than conventional T cells. The TILs-ACT combined with PD-1 inhibitor promoted active T-cell infiltration into the tumour tissue and exerted a strong antitumour effect in an in vivo model. Additionally, the strategy could downregulate the expression of inhibitory marker PD-1 on TILs. Our results suggested that PD-1 blockade regulated T-cell exhaustion which synergised with adoptive TIL transfer immunotherapy, leading to eradication of established TNBC tumours. These findings might be useful in developing a feasible and effective therapeutic approach for TNBC.

scholarly journals F1012-2 Induced ROS-Mediated DNA Damage Response through Activation of MAPK Pathway in Triple-Negative Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Lingjie Dai ◽  
Shasha Tian ◽  
Jinyao Zhang ◽  
Mengyuan Lu ◽  
Jingchao Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Migration And Invasion

We have previously reported that F1012-2, a sesquiterpene lactone isolated from the Chinese herbal medicine Eupatorium lindleyanum DC., exhibits strong effects against Triple Negative Breast Cancer (TNBC). In this study, we found F1012-2 effectively inhibited cell migration and invasion detected by wound healing and transwell assays. In order to elucidate the potential mechanisms of F1012-2, we further studied its effect on DNA damage in TNBC cell lines. Using single cell gel electrophoresis (comet assay), immunofluorescence, and western blotting assays, we found that F1012-2 treatment induced significant DNA strand breaks and γ-H2AX activation. Moreover, exposure to F1012-2 led to overproduction of reactive oxygen species (ROS). NAC treatment completely eliminated ROS, which may be due to the interaction between NAC and F1012-2. A further study of the molecular mechanisms demonstrated that the MAPK signaling pathway participated in the anti-TNBC effect of F1012-2. Pretreatment with specific inhibitors targeting JNK (SP600125) and ERK (PD98059) could rescue the decrease in cell viability and inhibit expressions of JNK and ERK phosphorylation, but SB203580 had no effects. Finally, in the acute toxicity experiment, there were no obvious symptoms of poisoning in the F1012-2 treatment group. An in vivo study demonstrated that F1012-2 significantly suppressed the tumor growth and induced DNA damage. In conclusion, the activity of F1012-2-induced DNA damage in TNBC was found in vivo and in vitro, which might trigger the MAPK pathway through ROS accumulation. These results indicate that F1012-2 may be an effective anti-TNBC therapeutic agent.

scholarly journals Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jung Ok Lee ◽  
Min Ju Kang ◽  
Won Seok Byun ◽  
Shin Ae Kim ◽  
Il Hyeok Seo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Anticancer Effect ◽  
Anticancer Effects ◽  
4T1 Breast Cancer

Abstract Background Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

scholarly journals MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jhih-Kai Pan ◽  
Cheng-Han Lin ◽  
Yao-Lung Kuo ◽  
Luo-Ping Ger ◽  
Hui-Chuan Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Survival Outcomes ◽  
Poor Survival ◽  
Breast Cancer Brain Metastasis ◽  
High Level

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

scholarly journals Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

2021 ◽  
Vol 7 (3) ◽  
pp. eabc4897
Author(s):  
Catríona M. Dowling ◽  
Kate E. R. Hollinshead ◽  
Alessandra Di Grande ◽  
Justin Pritchard ◽  
Hua Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Mitochondrial Apoptosis ◽  
Glycolytic Metabolism ◽  
Set Up ◽  
Screening Approaches

Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a “hit” compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.

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