Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer

Yamashita, Yuji; Nishiumi, Shin; Kono, S; Takao, Shintaro; Azuma, Takeshi; Yoshida, Masaru

doi:10.1186/s12885-017-3554-4

Cited by 69 publications

(62 citation statements)

References 44 publications

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“…Elongation of saturated FAs is mediated by ELOVL 1-7 [58]. ELOVL 1 and 6 mRNA levels were up-regulated in TNBC when compared with the luminal A subtype and up-regulated in both compared with normal tissue [59]. This suggests that the increase in PC � C-40 in TNBC cell lines may be explained by an increased production of long-chain FAs.…”

Section: Increased Phosphatidylcholine Synthesis In Triple Negative Bmentioning

confidence: 92%

Lipidomic study of cell lines reveals differences between breast cancer subtypes

et al. 2020

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Breast cancer (BC) is the most prevalent type of cancer in women in western countries. BC mortality has not declined despite early detection by screening, indicating the need for better informed treatment decisions. Therefore, a novel noninvasive diagnostic tool for BC would give the opportunity of subtype-specific treatment and improved prospects for the patients. Heterogeneity of BC tumor subtypes is reflected in the expression levels of enzymes in lipid metabolism. The aim of the study was to investigate whether the subtype defined by the transcriptome is reflected in the lipidome of BC cell lines. A liquid chromatography mass spectrometry (LC-MS) platform was applied to analyze the lipidome of six cell lines derived from human BC cell lines representing different BC subtypes. We identified an increased abundance of triacylglycerols (TG) � C-48 with moderate or multiple unsaturation in fatty acyl chains and down-regulated ether-phosphatidylethanolamines (PE) (C-34 to C-38) in cell lines representing estrogen receptor and progesterone receptor positive tumor subtypes. In a cell line representing HER2-overexpressing tumor subtype an elevated expression of TG (� C-46), phosphatidylcholines (PC) and PE containing short-chained (� C-16) saturated or monounsaturated fatty acids were observed. Increased abundance of PC � C-40 was found in cell lines of triple negative BC subtype. In addition, differences were detected in lipidomes within these previously defined subtypes. We conclude that subtypes defined by the transcriptome are indeed reflected in differences in the lipidome and, furthermore, potentially biologically relevant differences may exist within these defined subtypes.

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Section: Increased Phosphatidylcholine Synthesis In Triple Negative Bmentioning

confidence: 92%

Lipidomic study of cell lines reveals differences between breast cancer subtypes

et al. 2020

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“…The RB model 7, however, on an average, had 27% reduced flux through synthesis of only C22:4 and C22:5 fatty acids. Chain length of very long-chain fatty acids has been reported to be used for differentiating between cancer types [63]. Furthermore, metabolic profiling of retinoblastomas revealed that certain RB groups had increased lipids as compared to other RB groups that exhibited very low lipid concentrations [14].…”

Section: Long-chain Fatty Acid Synthesismentioning

confidence: 99%

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

et al. 2018

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Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint‐based reconstruction and analysis approaches to identify and explain RB‐specific survival strategies, which are RB tumor specific. Importantly, our model‐specific secretion profile is also found in RB1‐depleted human retinal cells in vitro and suggests that novel biomarkers involved in lipid metabolism may be important. Finally, RB‐specific synthetic lethals have been predicted as lipid and nucleoside transport proteins that can aid in novel drug target development.

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“…5D; Table 3) included: (1) YTA7/ATAD2/ATAD2B , which localizes to chromatin and regulates histone gene expression. ATAD2 overexpression portends poor prognosis in gastric, colorectal, cervical, hepatocellular carcinoma, lung, and breast cancer, and thus overexpression sensitivity could represent the potential to target a driver gene [119-125]; (2) PIF1 / PIF1 , a DNA helicase, which is involved in telomere regulation and is required during oncogenic stress [113]; (3) RPS1B/RPS3A , which is a small subunit ribosomal protein that is overexpressed in hepatitis B associated hepatocellular carcinoma and non-small cell lung cancer [114,115]; (4) LEO1/LEO1 , which associates with the RNA polymerase II and acts as an oncogene in acute myelogenous leukemia [156]; (5) ELO3/ELOVL1/ELOVL2/ ELOVL4/ELOVL6 , which constitutes a family of fatty acid elongases that function in sphingolipid biosynthesis, among which ELOVL1 is overexpressed in breast and colorectal cancer tissue [107,108], ELOVL2 is upregulated in hepatocellular carcinoma [109], and ELOVL6 is overexpressed and associated with poor prognosis in liver and breast cancer [110,111] ; (6) MDL2/ABCB10 , which is a mitochondrial inner membrane ATP-binding cassette protein and is upregulated in breast cancer [112]; (7) CPR3/PPIA , which is a mitochondrial cyclophilin that is upregulated in lung cancer, esophageal, and pancreatic cancer [104-106]; and (8) SAC3/MCM3AP/SAC3D1 , which is a nuclear pore-associated protein functioning in transcription and mRNA export, with MCM3AP being upregulated in glioma cells [116], while SAC3D1 is upregulated in cervical cancer and hepatocellular carcinoma [117,118]. Yeast gene deletion suppression together with overexpression sensitivity of human homologs in cancer reveals potential therapeutic vulnerabilities that can be further explored in both systems.…”

Section: Resultsmentioning

confidence: 99%

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

Santos

Icyuz

Pound

et al. 2019

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10Knowledge about synthetic lethality can be applied to enhance the efficacy of 11 anti-cancer therapies in individual patients harboring genetic alterations in their cancer 12 that specifically render it vulnerable. We investigated the potential for high-resolution 13 phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, 14 comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine 15 and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures 16 yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally 17 expressed in the S. cerevisiae genomic library of knockout and knockdown (YKO/KD) 18 strains, to globally and quantitatively characterize differential drug-gene interaction for 19 gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, 20 histone modification, chromatin remodeling, and apoptosis-related processes influence 21 gemcitabine specifically, while drug-gene interaction specific to cytarabine was less 22 enriched in Gene Ontology. Processes having influence over both drugs were DNA 23 repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched 24 genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics 25 data were integrated to identify yeast-human homologs with correlated differential gene 26 2 expression and drug-efficacy, thus providing a unique resource to predict whether 27 differential gene expression observed in cancer genetic profiles are causal in tumor-28 specific responses to cytotoxic agents. 29 30 Keywords: 31 yeast phenomics, gene-drug interaction, genetic buffering, quantitative high 32 throughput cell array phenotyping (Q-HTCP), cell proliferation parameters (CPPs), 33 gemcitabine, cytarabine, recursive expectation-maximization clustering (REMc), 34 pharmacogenomics 35 36 Introduction: 37Genomics has enabled targeted therapy aimed at cancer driver genes and 38 oncogenic addiction [1], yet traditional cytotoxic chemotherapeutic agents remain among 39 the most widely used and efficacious anti-cancer therapies [2]. Changes in the genetic 40 network underlying cancer can produce vulnerabilities to cytotoxic chemotherapy that 41 further influence the therapeutic window and provide additional insight into their 42 mechanisms of action [3,4]. A potential advantage of so-called synthetic lethality-based 43 treatment strategies is that they could have efficacy against passenger gene mutation or 44 compensatory gene expression, while classic targeted therapies are directed primarily at 45 driver genes ( Fig. 1A). Quantitative high throughput cell array phenotyping of the yeast 46 knockout and knockdown libraries provides a phenomic means for systems level, high- 47resolution modeling of gene interaction [5][6][7][8][9], which is applied here to predict cancer-48 relevant drug-gene interaction through integration with cancer pharmacogenomics 49 resources ( Fig. 1B). 50Nucleoside analogs include a diverse group of co...

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Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer

Cited by 69 publications

References 44 publications

Lipidomic study of cell lines reveals differences between breast cancer subtypes

Lipidomic study of cell lines reveals differences between breast cancer subtypes

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

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