Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

Alasmael, Noura; Mohan, R.; Meira, Lisiane B.; Swales, Karen E.; Plant, Nick

doi:10.1016/j.canlet.2015.10.031

Cited by 32 publications

(22 citation statements)

References 48 publications

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“…Other studies have shown FXR protein expression in these cell lines and tumors using Western blot analysis and IHC (27,(44)(45)(46). As a general finding, FXR signaling in these cell lines led to oncosuppressive effects (27,44,45). Consistent with these observations, high FXR expression in human breast tumors was associated with favorable patient survival in one analysis (46).…”

Section: Discussionsupporting

confidence: 67%

“…S8). Other studies have shown FXR protein expression in these cell lines and tumors using Western blot analysis and IHC (27,(44)(45)(46). As a general finding, FXR signaling in these cell lines led to oncosuppressive effects (27,44,45).…”

Section: Discussionmentioning

confidence: 65%

“…Others reported that DC promotes survival of MDA-MB-231 and 4T1 breast cancer cells (41,42). In contrast, antitumor effects, including inhibition of growth, were observed by different investigators (27)(28)(29). One of these studies reported decreased long-term survival of CDCand DC-treated MCF-7 cells and destabilization of HIF1a (28).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple studies previously examined effects of bile acids on cancer cell growth and reported both pro-and antiproliferative effects of these bile acids in different cancer cell models including breast cancer (25)(26)(27)(28)(29). To revisit this question and to obtain further clarification whether bile acids are growth-inhibitory in breast cancer cells, four luminal A breast cancer cell lines, MCF7, Figure 4.…”

Section: Bile Acids Inhibit Proliferation Of Human Breast Cancer Cellsmentioning

confidence: 99%

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Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Tang

Putluri

Ambati

et al. 2019

Clinical Cancer Research

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Purpose: Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology. Experimental Design: We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments. Results: LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G 2-M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors. Conclusions: We describe the unexpected accumulation of liver-and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Bile Acids Inhibit Proliferation Of Human Breast Cancer Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Tang

Putluri

Ambati

et al. 2019

Clinical Cancer Research

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“…LXR activation is known to inhibit proliferation of breast cancer cells 53 and FXR activation in breast cancer cells results in cytotoxicity. 54 Activated FXR can also counteract the tumour promoting ability of cancer-associated fibroblasts within the breast cancer microenvironment. 55 Therefore, one might hypothesise that the removal of LXR and FXR pathway components in control cell EVs suggests that normal proliferation occurs.…”

Section: Discussionmentioning

confidence: 99%

Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells

et al. 2017

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Triple negative breast cancer (TNBC) is an aggressive subtype with relatively poor clinical outcomes and limited treatment options. Chemotherapy, while killing cancer cells, can result in the generation of highly chemoresistant therapeutic induced senescent (TIS) cells that potentially form stem cell niches resulting in metastases. Intriguingly, senescent cells release significantly more extracellular vesicles (EVs) than non-senescent cells. Our aim was to profile EVs harvested from TIS TNBC cells compared with control cells to identify a potential mechanism by which TIS TNBC cells maintain survival in the face of chemotherapy. TIS was induced and confirmed in Cal51 TNBC cells using the chemotherapeutic paclitaxel (PTX) (Taxol). Mass spectrometry (MS) analysis of EVs harvested from TIS compared with control Cal51 cells was performed using Ingenuity Pathway Analysis and InnateDB programs. We demonstrate that TIS Cal51 cells treated with 75 nM PTX for 7 days became senescent (senescence-associated β-galactosidase (SA-β-Gal) positive, Ki67-negative, increased p21 and p16, G2/M cell cycle arrest) and released significantly more EVs (P=0.0002) and exosomes (P=0.0007) than non-senescent control cells. Moreover, TIS cells displayed an increased expression of the multidrug resistance protein 1/p-glycoprotein. MS analysis demonstrated that EVs derived from senescent Cal51 cells contained 142 proteins with a significant increased fold change compared with control EVs. Key proteins included ATPases, annexins, tubulins, integrins, Rabs and insoluble senescence-associated secretory phenotype (SASP) factors. A fluorescent analogue of PTX (Flutax-2) allowed appreciation of the removal of chemotherapy in EVs from senescent cells. Treatment of TIS cells with the exosome biogenesis inhibitor GW4869 resulted in reduced SA-β-Gal staining (P=0.04). In summary, this study demonstrates that TIS cells release significantly more EVs compared with control cells, containing chemotherapy and key proteins involved in cell proliferation, ATP depletion, apoptosis and the SASP. These findings may partially explain why cancer senescent cells remain viable despite chemotherapeutic challenge.

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Construction and Validation of a Prognostic Model Based on Novel Senescence‐Related Genes in Non‐Small Cell Lung Cancer Patients with Drug Sensitivity and Tumor Microenvironment

et al. 2023

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Cellular senescence contributes to cancer pathogenesis and immune regulation. Using the LASSO Cox regression, we developed a 12‐gene prognostic signature for lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) and a Gene Expression Omnibus (GEO) dataset. We assessed gene expression, drug sensitivity, immune infiltration, and conducted cell line experiments. High‐risk LUAD patients showed increased mortality risk and shorter survival (P < 0.001). Senescence‐related gene analysis indicated differences in protein phosphorylation and DNA methylation between normal individuals and LUAD patients. The high‐risk group showed a positive association with PD‐L1 expression (P = 0.003). Single‐cell sequencing data suggested PEBP1 might significantly impact T cell infiltration. We predicted potential sensitive compounds for 12 senescence genes and found GAPDH promoted cell line proliferation. We established a novel prognostic system based on a newly identified senescence gene. High‐risk patients had elevated immunosuppressive markers, and PEBP1 might influence T cell infiltration significantly. GAPDH, expressed at higher levels in tumors, could affect cancer progression. Our drug prediction model may guide treatment selection.

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Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

Abstract: Breast cancer is the commonest form of cancer in women, but successful treatment is

Cited by 32 publications

References 48 publications

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival

Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells

Construction and Validation of a Prognostic Model Based on Novel Senescence‐Related Genes in Non‐Small Cell Lung Cancer Patients with Drug Sensitivity and Tumor Microenvironment

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