Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

Ehmsen, Sidse; Pedersen, Martin Haar; Wang, Guisong; Terp, Mikkel Green; Arslanagic, Amina; Hood, Brian L.; Conrads, Thomas P.; Leth-Larsen, Rikke; Ditzel, Henrik J.

doi:10.1016/j.celrep.2019.05.104

Cited by 133 publications

(119 citation statements)

References 58 publications

(62 reference statements)

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“…Also in this case, analysis of affected signaling processes performed on a lists of deregulated miRNA targets revealed mainly histotype-specific changes, with the only common group of signaling pathways consisting of all branches of cholesterol biosynthesis, in line with our previous results concerning ERβ-induced inhibition of cholesterol biosynthesis in TNBC [15]. Moreover, one recently published study demonstrated that cholesterol biosynthesis is essential for breast cancer stem cell propagation [77], whereas another showed that the hyper-activated cholesterol biosynthesis program of TNBC is regulated by nuclear receptor RORγ (RAR-related orphan receptor gamma), whose inhibition by receptor antagonists leads to tumor regression in patient-derived xenografts and immune-intact models [78], confirming the extreme importance of cholesterol biosynthesis in TNBC cancer progression.…”

Section: Discussionsupporting

confidence: 88%

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Alexandrova

Lamberti

Saggese

et al. 2020

Cells

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Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.

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Section: Discussionsupporting

confidence: 88%

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Alexandrova

Lamberti

Saggese

et al. 2020

Cells

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“…cholesterol and lipid rafts (41,57). In addition, recent data revealed the activation of cholesterol biosynthesis pathways in cancer stem cells (42) Heterogeneity of glioma determined by TOF-SIMS 20 the clinical and histological features of the tumor, and in some cases, it allows to subdivide patients into groups characterized by more favorable and less favorable survival. Since TOF-SIMS does not require specific sample preparation procedures, and the analysis of one sample takes less than 10 minutes, it is possible that after further development this technology can be used for the rapid identification of GBM cells.…”

Section: Discussionmentioning

confidence: 99%

“…These data are in good agreement with our hypothesis that the cholesterol high /Caveolin-1 high population of GBM cells found using TOF-SIMS may represent GSC. This hypothesis is also indirectly supported by the fact that cancer stem cells are characterized by an increased level of cholesterol biosynthesis (42).…”

Section: Detection Of Caveolin-1 Protein and Cholesterol In Gbm Cellsmentioning

confidence: 94%

Investigation of Inter- and Intratumoral Heterogeneity of Glioblastoma Using TOF-SIMS

Gularyan

Гулин

Anufrieva

et al. 2020

Molecular & Cellular Proteomics

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Glioblastoma (GBM) is one of the most aggressive human cancers with a median survival of less than two years. A distinguishing pathological feature of GBM is a high degree of inter- and intratumoral heterogeneity. Intertumoral heterogeneity of GBM has been extensively investigated on genomic, methylomic, transcriptomic, proteomic and metabolomics levels, however only a few studies describe intratumoral heterogeneity because of the lack of methods allowing to analyze GBM samples with high spatial resolution. Here, we applied TOF-SIMS (Time-of-flight secondary ion mass spectrometry) for the analysis of single cells and clinical samples such as paraffin and frozen tumor sections obtained from 57 patients. We developed a technique that allows us to simultaneously detect the distribution of proteins and metabolites in glioma tissue with 800 nm spatial resolution. Our results demonstrate that according to TOF-SIMS data glioma samples can be subdivided into clinically relevant groups and distinguished from the normal brain tissue. In addition, TOF-SIMS was able to elucidate differences between morphologically distinct regions of GBM within the same tumor. By staining GBM sections with gold-conjugated antibodies against Caveolin-1 we could visualize border between zones of necrotic and cellular tumor and subdivide glioma samples into groups characterized by different survival of the patients. Finally, we demonstrated that GBM contains cells that are characterized by high levels of Caveolin-1 protein and cholesterol. This population may partly represent a glioma stem cells. Collectively, our results show that the technique described here allows to analyze glioma tissues with a spatial resolution beyond reach of most of other omics approaches and the obtained data may be used to predict clinical behavior of the tumor.

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“…Cholesterol biosynthesis also has a critical role in maintaining cancer stem cells by activating cellular signalling pathways downstream of sonic hedgehog, Notch and receptor tyrosine kinases 30 . Furthermore, elevated cholesterol biosynthesis is observed in patient-derived cancer stem cells under mammosphere culture conditions 31 . These lines of evidence suggest that ensuring a sufficient cholesterol supply for the cancer stem cell population may be essential to support cancer progression, thus highlighting a fundamental role of cholesterol in cancer cells.…”

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confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

Abstract: Highlights d Cholesterol biosynthesis is essential for breast cancer stem cell propagation d Expression of cholesterol synthesis proteins correlates with TNBC patient outcome d Inhibition of cholesterol biosynthesis reduces mammosphere formation

Cited by 133 publications

References 58 publications

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Investigation of Inter- and Intratumoral Heterogeneity of Glioblastoma Using TOF-SIMS

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

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