Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

Eustace, Alex J.; Lee, Min Jie; Colley, Grace; Roban, Jack; Downing, Tim; Buchanan, Paul

doi:10.20517/cdr.2022.41

Cited by 6 publications

(3 citation statements)

References 151 publications

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“…These intracellular pathways are not independent of BC. PI3K-Akt is a major signaling pathway that is involved in regulating cell proliferation, survival, and metabolism, but is often the most activated oncogenic pathway in triple-negative breast cancer (TNBC) [29][30][31] . Therefore, clinical trials based on PI3K-Akt inhibition are currently underway 32) .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Membrane <i>N</i>-Glycoproteomics Using Human Breast Cancer Cell Line Pairs

et al. 2023

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Aberrant glycosylation of membrane proteins is a hallmark of cancer and a useful molecular marker for the diagnosis of breast cancer (BC). However, the molecular mechanisms by which altered glycosylation affects the malignant transformations associated with BC are poorly understood.Accordingly, we performed comparative membrane N-glycoproteomics using the human BC cell line pair, Hs578T, and its syngeneic normal cell line, Hs578Bst. A total of 359 N-glycoforms derived from 113 proteins were identified in both cell lines, of which 27 were found only in Hs578T cells.Significant changes in N-glycosylation were found in the lysosome-associated membrane protein 1 (LAMP1), the integrin family, and laminin. Confocal immunofluorescence microscopy images revealed the accumulation of lysosomes in the perinuclear space in cancer cells, which could be associated with marked changes in LAMP1 glycosylation, such as a decreased level of Site-specific glycosylation change in BC 2 Mass Spectrometry Advance Publication polylactosamine chains. Overall, the alterations in glycosylation may be involved in changes in the adhesion and degradation of BC cells.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Membrane <i>N</i>-Glycoproteomics Using Human Breast Cancer Cell Line Pairs

et al. 2023

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“…[32] TNBC harbors PI3K mutations that may trigger disease progression and therapy resistance. [34,35] Activation of the PI3K/AKT pathway has been reported to induce chemotherapeutic resistance in TNBC. Moreover, our low-risk group showed higher TMBs.…”

Section: Discussionmentioning

confidence: 99%

Prognostic correlation and immune characteristics of a TAM cluster- related 8-gene risk signature in triple-negative breast cancer

Miao

Bian

Wang³

et al. 2023

Preprint

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Tumor-associated macrophages (TAMs) play a critical role in the progression of and immune response to triple-negative breast cancer (TNBC). This study aimed to explore the features of TAMs in TNBCs, construct a risk signature associated with TAM clusters, and verify their relationship with prognosis and immune-related characteristics. Primarily, we selected four TAM clusters and determined the prognosis-related clusters in TNBC based on single-cell RNA sequencing data. Subsequently, TAM-related prognostic genes were identified by univariate Cox regression analysis and an 8-genes risk signature was constructed by LASSO regression. The analysis of immune characteristics showed a significant association between the gene signature and stromal and immune scores as well as immune cells. Multivariate analysis revealed that the risk signature was an independent prognostic factor for TNBC, and confirmed its predictive value for immunotherapeutic outcomes. The newly constructed nomogram integrating stage and TAM-based risk signatures exhibited favorable predictability and reliability for TNBC prognosis prediction. Finally, the increased expression of GPR34, one of the eight hub genes, was explored in TNBC using reverse-transcriptase polymerase chain reaction, western blot, and immunohistochemistry. Our study may allow discovering new independent prognostic factors, updating immunotherapeutic methods, and identifying effective therapeutic targets for TNBC.

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“…TP53 mutations may result in overactivation of the PIK3CA and PI3K signalling pathways [33]. AKT can phosphorylate Hdm2 to improve its function, and there is evidence that PTEN can prevent TP53 degradation by inhibiting AKT activation [34]. Pathological damage was found in the intestine, liver, and brain of mice in the Dense Fruit Pitney Root-Bark group, and the contents of AKT1, JUN, RELA, SRC, and TP53 in the intestine, liver, and brain increased signi cantly, suggesting that the mechanism of Dense Fruit Pitney Root-Bark's toxicity to the intestine, liver, and brain may be activation of AKT1, JUN, RELA, SRC,the detailed mechanism diagram is shown in Fig.…”

Section: Analysis Of Interaction Between Small Molecules and Proteinsmentioning

confidence: 99%

A Study to Explore the Substance Basis and Mechanism of Action of the Potential Intestinal-Hepatic-Brain Toxicity of Densefruit Pittany Root-Bark Based on Toxicological Evidence Chain (TEC)

Xu,

Sun,

Wang

et al. 2023

Preprint

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Background Densefruit pittany root-bark is derived from the dried root bark of rutaceae Baixian, a traditional Chinese medicine widely used to treat eczema, psoriasis, and other skin diseases in China. However, in recent years, there have been an increasing number of reports about its negative effects. The potential toxic components and targets of densefruit pittany root-bark intestinal-liver-brain toxicity were screened in this study using pharmacochemistry and network drug/toxicology, molecular docking and molecular dynamics simulation, and were verified by evidence of adverse outcome (AOE).Methods HPLC was used to characterise the densefruit pittany root-bark.TCMSP, TCM-ID, TCM@Taiwan, and CTD databases are used to filter Densefruit pittany root-bark. PharmMapper, SwissTargetPrediction, GeneCards, DisGeNET, and OMIM databases were used to predict the targets of Dense Fruit Root-Bark-induced intestinal-liver-brain tissue damage, and the intersecting targets were chosen for PPI protein interaction analysis, KEGG pathway analysis, and GO enrichment analysis. To depict the core regulatory network, a "drug-compound-toxic target-pathway" map was created using Cytoscape software. The binding affinity and reliability were investigated using molecular docking and molecular dynamics simulation. Finally, HPLC, HE staining, immunohistochemistry, and WB were used to confirm AOE.Results Three compounds in densefruit pittany root-bark were tested, and 125 targets were found to be related to the intestinal-liver-brain toxicity caused by Dense fruit pittance root-bark. The primary targets, according to PPI network analysis, were AKT1, JUN, RELA, SRC, and TP53.Furthermore, GO/KEGG enrichment analysis revealed that densefruit pittany root-bark may modulate Lipid and atherosclerosis, fluid shear stress and atherosclerosis, and the TNF signalling pathway to cause intestinal-liver-brain tissue injury. According to the "herb-compound-toxic target-pathway-organ damage" network, dictamine, obakunone, and fraxinone may be therapeutic or main toxic compounds. Molecular docking and molecular dynamics simulation results show that the core compound has a high affinity for the target.Conclusion This study clarified the mechanism of densefruit pittany root-bark-induced intestinal-liver-brain toxicity, which was the first study on the toxicity of densefruit pittany root-bark based on the concept of TEC, and provided a reference for future research on the toxicity mechanism of densefruit pittany root-bark. However, further experimental validation is required before using densefruit pittany root-bark in clinical practise.

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Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

Cited by 6 publications

References 151 publications

Comprehensive Membrane <i>N</i>-Glycoproteomics Using Human Breast Cancer Cell Line Pairs

Comprehensive Membrane <i>N</i>-Glycoproteomics Using Human Breast Cancer Cell Line Pairs

Prognostic correlation and immune characteristics of a TAM cluster- related 8-gene risk signature in triple-negative breast cancer

A Study to Explore the Substance Basis and Mechanism of Action of the Potential Intestinal-Hepatic-Brain Toxicity of Densefruit Pittany Root-Bark Based on Toxicological Evidence Chain (TEC)

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