Systems pharmacology in combination with proteomics reveals underlying mechanisms of Xihuang pill against triple-negative breast cancer

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

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A Quantitative Systems Pharmacology Framework for Optimal Doxorubicin Granulocyte Colony-Stimulating Factor Regimens in Triple-Negative Breast Cancer

Pharmacology ◽

10.1159/000518037 ◽

2021 ◽

pp. 1-9

Author(s):

Rosalba Vivian Paredes Bonilla ◽

Fahima Nekka ◽

Morgan Craig

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Tumour Growth ◽

Triple Negative ◽

Effective Control ◽

Systems Pharmacology ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Quantitative Systems Pharmacology ◽

Stimulating Factor

Introduction: To mitigate the risk of neutropenia during chemotherapy treatment of triple-negative breast cancer, prophylactic and supportive therapy with granulocyte colony-stimulating factor (G-CSF) is administered concomitant to chemotherapy. The proper timing of combined chemotherapy and G-CSF is crucial for treatment outcomes. Methods: Leveraging our established mathematical model of neutrophil production by G-CSF, we developed quantitative systems pharmacology (QSP) framework to investigate how modulating chemotherapy dose frequency and intensity can maximize antitumour effects. To establish schedules that best control tumour size while minimizing neutropenia, we combined Gompertzian tumour growth with pharmacokinetic/pharmacodynamic models of doxorubicin and G-CSF, and our QSP model of neutrophil production. Results: We optimized a range of chemotherapeutic cycle lengths and dose sizes to establish regimens that simultaneously reduced tumour burden while minimizing neutropenia. Our results suggest that cytotoxic chemotherapy with doxorubicin 45 mg/m2 every 14 days provides effective control of tumour growth while mitigating neutropenic risks. Conclusion: This work suggests future avenues for optimal regimens of chemotherapy with prophylactic G-CSF support. Importantly, the algorithmic approach that we developed can aid in balancing the anticancer and the neutropenic effects of both drugs, and therefore contributes to rational considerations in clinical decision-making in triple-negative breast cancer.

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LncRNA PCIR Is an Oncogenic Driver via Strengthen the Binding of TAB3 and PABPC4 in Triple Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.630300 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wenhui Guo ◽

Jingyi Li ◽

Haobo Huang ◽

Fangmeng Fu ◽

Yuxiang Lin ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Migration And Invasion ◽

Tnf Α ◽

Associated Proteins ◽

Rna Immunoprecipitation ◽

Underlying Mechanisms

Long non-coding RNAs (LncRNA) as the key regulators in all stages of tumorigenesis and metastasis. However, the underlying mechanisms are largely unknown. Here, we report a lncRNA RP11-214F16.8, which renamed Lnc-PCIR, is upregulated and higher RNA level of Lnc-PCIR was positively correlated to the poor survival of patients with triple negative breast cancer (TNBC) tissues. Lnc-PCIR overexpression significantly promoted cell proliferation, migration, and invasion in vitro and in vivo. RNA pulldown, RNA immunoprecipitation (RIP) and RNA transcriptome sequencing technology (RNA-seq) was performed to identify the associated proteins and related signaling pathways. Mechanistically, higher Lnc-PCIR level of blocks PABPC4 proteasome-dependent ubiquitination degradation; stable and highly expressed PABPC4 can further increase the stability of TAB3 mRNA, meanwhile, overexpression of Lnc-PCIR can disrupt the binding status of TAB3 and TAB2 which lead to activate the TNF-α/NF-κB pathway in TNBC cells. Our findings suggest that Lnc-PCIR promotes tumor growth and metastasis via up-regulating the mRNA/protein level of TAB3 and PABPC4, activating TNF-α/NF-κB signaling pathway in TNBC.

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Correction: Quantitative systems pharmacology model predictions for efficacy of atezolizumab and nab-paclitaxel in triple-negative breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002100corr1 ◽

2021 ◽

Vol 9 (10) ◽

pp. e002100corr1

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Systems Pharmacology ◽

Quantitative Systems Pharmacology ◽

Model Predictions ◽

Systems Pharmacology Model

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PARP inhibitor increases chemosensitivity by upregulating miR-664b-5p in BRCA1-mutated triple-negative breast cancer

Scientific Reports ◽

10.1038/srep42319 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 9

Author(s):

Wei Song ◽

Lin Tang ◽

Yumei Xu ◽

Jing Xu ◽

Wenwen Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Migration And Invasion ◽

Therapy Regimen ◽

Xenograft Models ◽

Underlying Mechanisms

Abstract Emerging evidence has shown that adding poly(ADP-ribose) polymerase (PARP) inhibitors to chemotherapy regimens is superior to the control regimens alone in BRCA1-mutated triple-negative breast cancer (TNBC) patients, but their underlying mechanisms have not been fully elucidated. In this study, using miRNA microarray analysis of two BRCA1-mutated TNBC cell lines, we found that miR-664b-5p expression was increased after adding a PARP inhibitor, olaparib, to a carboplatin (CBP) plus gemcitabine (GEM) therapy regimen. Functional assays showed miR-664b-5p overexpression inhibited proliferation, migration and invasion in BRCA1-mutated TNBC cells. CCNE2 was identified as a novel functional target of miR-664b-5p, and CCNE2 knockdown revealed effects similar to those observed with miR-664b-5p overexpression. Both CCNE2 knockdown and miR-664b-5p overexpression significantly increased the chemosensitivity of BRCA1-mutated TNBC cells. In addition, in vivo studies indicated that miR-664b-5p inhibited tumour growth compared with the control in tumour xenograft models, and we also found that CCNE2 expression was inversely correlated with miR-664b-5p expression in 90 TNBC patient samples. In conclusion, miR-664b-5p functions as a tumour suppressor and has an important role in the regulation of PARP inhibitors to increase chemosensitivity by targeting CCNE2. This may be one of the possible mechanisms by which PARP inhibitors increase chemosensitivity in BRCA1-mutated TNBC.

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BAI1 Acts as a Tumor Suppressor in Triple-Negative Breast Cancer via Modulating p73 Transactivation

10.21203/rs.3.rs-60195/v1 ◽

2020 ◽

Author(s):

Xia yang ◽

Ping Wei ◽

Ruohong Shui

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Triple Negative Breast Cancer ◽

Cell Apoptosis ◽

Transcriptional Activity ◽

Triple Negative ◽

Cycle Arrest ◽

Underlying Mechanisms

Abstract Background: Brain-specific angiogenesis inhibitor 1 (BAI1) which belongs to putative G-protein-coupled receptors (GPCRs), has been found down-expressed in various cancers and involved in cancer pathogenesis. However, the role and underlying mechanisms of BAI1 in triple negative breast cancer (TNBC) are still unclear. Methods: The expression levels of BAI1 in TNBC samples and cell lines were examined by immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting (WB). The functional effects of BAI1 on biological behaviors of TNBC cells were detected using plasmid and siRNA for BAI1 overexpression and knockdown, and the underlying mechanisms were investigated by Immunoprecipitation (IP), immunofluorescence (IF) and luciferase reporter assay. Results: BAI1 was downregulated in TNBC tissues and was significantly associated with poor disease-free survival. Functional experiments indicated that BAI1 inhibited cell proliferation and induced cell apoptosis and cell cycle arrest. Additionally, BAI1 overexpressed cells were more sensitive to cisplatin. Mechanistically, BAI1 interacted with MDM2, thereby enhanced p73 transcriptional activity, then promoted p21and BAX mRNA and protein expression. Overexpression of p73 abolished the BAI1 knockdown induced cell proliferation and the G2 phase cell population of TNBC, the sensitivity to cisplatin also rescued by overregulating p73 in BAI1 knockdown TNBC cells. Conclusions: Our results indicate that BAI1 is a promising prognostic factor in TNBC, and the expression of BAI1 inhibits cell proliferation and induces cell apoptosis and cell cycle arrest; Meanwhile, BAI1 increases the sensitivity of TNBC to cisplatin. For the underlying mechanism, BAI1 specifically binds to MDM2, and exerts its anti-tumor function by affecting the transcriptional activity of p73 protein, then inhibits the malignant progression of TNBC. The BAI1/MDM2/p73 axis may represent a potential target in the future research for TNBC.

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Q-TOF LC/MS-based Untargeted Metabolomics Approach to Evaluate the Effect of Folate-Conjugated Cyclodextrins on Triple-Negative Breast Cancer Cells

Current Pharmaceutical Analysis ◽

10.2174/1573412917999201020205745 ◽

2020 ◽

Vol 17 ◽

Author(s):

Işıl Varol ◽

Ozan Kaplan ◽

Nazlı Erdoğar ◽

Selin Öncül ◽

Thorbjorn Terndrup Nielsen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Driving Forces ◽

Morphological Examination ◽

Public Health Burden ◽

Mechanistic Approach ◽

Metabolic Mechanism ◽

Underlying Mechanisms

Background:: Breast cancer is a heterogenic disease that comprises various morphologies with intrinsic subtypes and is principally responsible for casualties among female cancer patients. Triple-negative breast cancer (TNBC) is the most aggressive subtype with a high probability of relapsing, hence successful treatment can be quite challenging. The pathogenesis of TNBC remains ambiguous and the identification of dependable biomarkers for its early diagnosis is crucial to design a strategy for therapeutic armamentarium. Objective:: To clarify the folate-dependent mechanism of action causing cell death and to unravel the potential biomarkers of TNBC to defeat this consequential public health burden. Methods:: The MTT assay and the morphological examination via microscopy were carried out to examine the viability of the cells upon the administration of the blank folate-conjugated cyclodextrin nanoparticles. An untargeted metabolomic approach using Q-TOF LC/MS was performed. Multivariate analysis of the metabolomic profile was applied to the MDAMB- 231 cell line with the aim of comparing the untreated cells with the folate-conjugated cyclodextrin nanoparticles applied cells to detect possible biomarkers. Results:: The spectrophotometric and microscopic analyses revealed that MDA-MB-231 cells underwent early apoptosis following the incubation with the folate-conjugated nanoparticles for 24 h of administration. Moreover, metabolomics profiling pointed out that the hexose metabolism was significantly altered. Data mining procedures showed that glycolysis, mannose, fructose, and galactose were the most affected pathways in TNBC upon blank folate-conjugated cyclodextrin nanoparticle administration and this effect was determined to be cell-specific. A perturbed hexose pathway may be the explanation of selective cell death and decelerated cell growth seen in TNBC cells. Conclusions:: Our study offer a new understanding of the underlying mechanisms of TNBC since we hereby provide evidence that hexose is one of the main driving forces for the metabolic mechanism over TNBC cells. This alternative mechanistic approach may markedly increase the effect of chemotherapy on TNBC.

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Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs/mRNAs and miRNAs with Associated ceRNA Networks in Triple-Negative Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000494162 ◽

2018 ◽

Vol 50 (2) ◽

pp. 473-488 ◽

Cited By ~ 17

Author(s):

Rui Yang ◽

Lei Xing ◽

Min Wang ◽

Hong Chi ◽

Luyu Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Large Scale ◽

Triple Negative ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

Cerna Network ◽

Malignant Breast ◽

Underlying Mechanisms

Background/Aims: Triple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. Growing evidence indicates that Long noncoding RNAs (lncRNAs) play important regulatory roles in the development and progression of a variety of cancers including breast cancer. However, the underlying mechanisms remain largely unknown. Methods: Here, we compared the expression profiles of mRNAs, lncRNAs and miRNAs between 111 TNBC tissues and 104 non-cancerous tissues utilizing RNA-Seq Data from The Cancer Genome Atlas (TCGA). Gene Ontology and KEGG pathway enrichment analyses were executed to investigate the principal functions of the significantly dysregulated mRNAs. Moreover, Kaplan-Meier survival analyses were performed to determine the effects of differentially expressed lncRNAs/mRNAs/miRNAs on overall survival. Subsequently, we constructed a competing endogenous RNA (ceRNA) network, which included 66 dysregulated lncRNAs, 24 miRNAs and 55 mRNAs. The four dysregulated lncRNAs, three aberrantly expressed miRNAs and four mRNAs were confirmed in the ceRNA network by qRT-PCR in 30 pairs of samples, respectively. Results: A total of 1441 lncRNAs, 114 miRNA and 2501 mRNAs were found to be differentially expressed in TNBC tissues compared with controls. 109 lncRNAs and 124 mRNAs might serve as prognostic signature for patients with TNBC according to the survival analysis. Functional analysis revealed that 19 mRNAs in the ceRNA network were enriched in 17 cancer-related pathways. Conclusion: Taken together, we identified novel lncRNAs/miRNAs which may serve as potential biomarkers to predict the survival and therapeutic targets for TNBC patients based on a large-scale sample. More importantly, we constructed the ceRNA network of TNBC, which provides valuable information to further explore the molecular mechanism underlying tumorigenesis and development of TNBC.

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Cantharidin Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing Autophagy and Inducing Apoptosis in Vitro and in Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000484069 ◽

2017 ◽

Vol 43 (5) ◽

pp. 1829-1840 ◽

Cited By ~ 23

Author(s):

Hong-chang Li ◽

Zhi-hua Xia ◽

Ya-feng Chen ◽

Fan Yang ◽

Wen Feng ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Nude Mice ◽

Triple Negative ◽

Beclin 1 ◽

Associated Proteins ◽

Potential Strategy ◽

Underlying Mechanisms

Background/Aims: Cantharidin, a type of terpenoid secreted by the blister beetle Mylabris phalerata (Pallas), has attracted great attention in cancer therapy because of its potential anti-cancer activities. Here, we report the effects on apoptosis and autophagy in human triple-negative breast cancer (TNBC) cell lines after treatment with cantharidin and attempt to elucidate the underlying mechanisms. Methods: MDA-MB-231 and MDA-MB-468 cells were treated with cantharidin and cell proliferation was examined using CCK-8 and clone formation assays. The expression of apoptosis- and autophagy-associated proteins was detected by western blotting. Cells were infected with lentivirus carrying the Beclin-1 gene, and MDA-MB-231-beclin1 (MB231-Bec) and MDA-MB-468-beclin-1(MB468-Bec) cells stably expressing Beclin-1 were established. Autophagic vacuoles in cells were observed with LC3 staining using fluorescence microscopy, and apoptotic cells were detected via flow cytometry. Tumor growth was assessed by subcutaneous inoculation of TNBC cells into BALB/c nude mice. Results: Cantharidin inhibited the proliferation of MDA-MB-231 and MDA-MB-468 cells, and induced cell apoptosis. Cantharidin additionally inhibited the conversion of LC3 I to LC3 II and autophagosome formation by suppressing the expression of Beclin-1. Furthermore, overexpression of Beclin-1 in TNBC cells attenuated the cytotoxicity of cantharidin. In vivo, cantharidin inhibited the growth of MDA-MB-231 and MDA-MB-468 xenografts in nude mice by suppressing autophagy and inducing apoptosis, and Beclin-1 overexpression in TNBC cells reduced the efficacy of cantharidin. Conclusions: Cantharidin inhibits autophagy by suppressing Beclin-1 expression and inducing apoptosis of TNBC cells in vitro and in vivo, thereby representing a potential strategy for the treatment of TNBC.

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