Multiplatform plasma metabolic and lipid fingerprinting of breast cancer: A pilot control-case study in Colombian Hispanic women

Breast cancer (BC) is a highly heterogeneous disease associated with metabolic reprogramming. The shifts in the metabolome caused by BC still lack data from Latin populations of Hispanic origin. In this pilot study, metabolomic and lipidomic approaches were performed to establish a plasma metabolic fingerprint of Colombian Hispanic women with BC. Data from 1H-NMR, GC-MS and LC-MS were combined and compared. Statistics showed discrimination between breast cancer and healthy subjects on all analytical platforms. The differentiating metabolites were involved in glycerolipid, glycerophospholipid, amino acid and fatty acid metabolism. This study demonstrates the usefulness of multiplatform approaches in metabolic/lipid fingerprinting studies to broaden the outlook of possible shifts in metabolism. Our findings propose relevant plasma metabolites that could contribute to a better understanding of underlying metabolic shifts driven by BC in women of Colombian Hispanic origin. Particularly, the understanding of the up-regulation of long chain fatty acyl carnitines and the down-regulation of cyclic phosphatidic acid (cPA). In addition, the mapped metabolic signatures in breast cancer were similar but not identical to those reported for non-Hispanic women, despite racial differences.

[1]  H. Degani,et al.  Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells. , 1996, Anticancer research.

[2]  H. Degani,et al.  Kinetics of choline transport and phosphorylation in human breast cancer cells; NMR application of the zero trans method. , 1996, Anticancer research.

[3]  J. Erickson,et al.  Glutaminase: A Hot Spot For Regulation Of Cancer Cell Metabolism? , 2010, Oncotarget.

[4]  H. Baloglu,et al.  Alterations of serum lipids and lipoproteins in breast cancer. , 1994, Cancer letters.

[5]  H. Gerstein,et al.  Establishing a relationship between prolactin and altered fatty acid β-Oxidation via carnitine palmitoyl transferase 1 in breast cancer cells , 2011, BMC Cancer.

[6]  James Ze Wang,et al.  Perioperative dynamics and significance of amino acid profiles in patients with cancer , 2015, Journal of Translational Medicine.

[7]  Matej Oresic,et al.  Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. , 2011, Cancer research.

[8]  Yang Liu,et al.  A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction , 2008, Molecular Cancer Therapeutics.

[9]  Takashi Ishikawa,et al.  Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection , 2011, PloS one.

[10]  D. Rose,et al.  Omega-3 fatty acids as cancer chemopreventive agents. , 1999, Pharmacology & therapeutics.

[11]  C. Townsend,et al.  Synthesis and antitumor activity of an inhibitor of fatty acid synthase. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Dwivedi,et al.  Total Cholesterol and Triglyceride Levels in Patients with Breast Cancer , 2013, Journal of breast cancer.

[13]  Yong-Ho Ahn,et al.  Up-regulation of Acetyl-CoA Carboxylase α and Fatty Acid Synthase by Human Epidermal Growth Factor Receptor 2 at the Translational Level in Breast Cancer Cells* , 2007, Journal of Biological Chemistry.

[14]  Phenotyping human blood plasma by 1H-NMR: a robust protocol based on metabolite spiking and its evaluation in breast cancer , 2015, Metabolomics.

[15]  Youping Deng,et al.  Plasma lipidomics profiling identified lipid biomarkers in distinguishing early-stage breast cancer from benign lesions , 2016, Oncotarget.

[16]  O. Warburg [Origin of cancer cells]. , 1956, Oncologia.

[17]  M. Ogawa,et al.  Overexpression of group II phospholipase A2 in human breast cancer tissues is closely associated with their malignant potency. , 1994, British Journal of Cancer.

[18]  Scha. Lipotoxicity: when tissues overeat , 2003 .

[19]  A. Habenicht,et al.  What are cyclooxygenases and lipoxygenases doing in the driver's seat of carcinogenesis? , 2006, International journal of cancer.

[20]  Kristian Hovde Liland,et al.  Multivariate methods in metabolomics – from pre-processing to dimension reduction and statistical analysis , 2011 .

[21]  Robert Powers,et al.  Multivariate Analysis in Metabolomics. , 2012, Current Metabolomics.

[22]  V. Vance,et al.  BRIEF COMMUNICATION Plasma amino acid profiles of breast cancer patients early in the trajectory of the disease differ from healthy comparison , 2014 .

[23]  E. Jobard,et al.  A serum nuclear magnetic resonance-based metabolomic signature of advanced metastatic human breast cancer. , 2014, Cancer letters.

[24]  R. Matsunuma,et al.  Human Breast Cancer Tissues Contain Abundant Phosphatidylcholine(36∶1) with High Stearoyl-CoA Desaturase-1 Expression , 2013, PloS one.

[25]  Guang Chen,et al.  Serum metabolomics analysis reveals changes in signaling lipids in breast cancer patients. , 2016, Biomedical chromatography : BMC.

[26]  W. Negendank,et al.  Studies of human tumors by MRS: A review , 1992, NMR in biomedicine.

[27]  P. Morris,et al.  Identification of a serum-detectable metabolomic fingerprint potentially correlated with the presence of micrometastatic disease in early breast cancer patients at varying risks of disease relapse by traditional prognostic methods. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  J. Wist,et al.  Coffee's country of origin determined by NMR: the Colombian case. , 2015, Food chemistry.

[29]  J. Schaffer,et al.  Lipotoxicity: when tissues overeat , 2003, Current opinion in lipidology.

[30]  M. Dutta,et al.  Comprehensive quantitative lipidomic approach to investigate serum phospholipid alterations in breast cancer , 2016, Metabolomics.

[31]  Y. Yen,et al.  Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients , 2013, International journal of molecular sciences.

[32]  V. Vance,et al.  Plasma amino acid profiles of breast cancer patients early in the trajectory of the disease differ from healthy comparison groups. , 2014, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[33]  Song Liu,et al.  Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes. , 2013, Translational oncology.

[34]  J. Chang,et al.  Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. , 2011, Chemistry & biology.

[35]  D Y Noh,et al.  Expression of phospholipase C-gamma 1 and its transcriptional regulators in breast cancer tissues. , 1998, Anticancer research.

[36]  Coral Barbas,et al.  In-vial dual extraction for direct LC-MS analysis of plasma for comprehensive and highly reproducible metabolic fingerprinting. , 2012, Analytical chemistry.

[37]  S. Husain,et al.  Role of lipids, lipoproteins and vitamins in women with breast cancer. , 2001, Clinical biochemistry.

[38]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[39]  A. Toker,et al.  Nonessential amino acid metabolism in breast cancer. , 2016, Advances in biological regulation.

[40]  Jianping Chen,et al.  Targeting FASN in Breast Cancer and the Discovery of Promising Inhibitors from Natural Products Derived from Traditional Chinese Medicine , 2014, Evidence-based complementary and alternative medicine : eCAM.

[41]  Rupasri Mandal,et al.  Cancer Metabolomics and the Human Metabolome Database , 2016, Metabolites.

[42]  M. Arbushites,et al.  Exploration of serum metabolomic profiles and outcomes in women with metastatic breast cancer: A pilot study , 2012, Molecular oncology.

[43]  S. Majid,et al.  Serum Lipid Profile of Breast Cancer Patients in Kashmir , 2013 .

[44]  Z. Bhujwalla,et al.  Choline phospholipid metabolism: A target in cancer cells? , 2003, Journal of cellular biochemistry.

[45]  Tanja Fehm,et al.  Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer , 2013, Molecular oncology.

[46]  Age K. Smilde,et al.  Assessing the performance of statistical validation tools for megavariate metabolomics data , 2006, Metabolomics.

[47]  Nissi M. Varki,et al.  Ras activation in human breast cancer , 2000, Breast Cancer Research and Treatment.

[48]  Y. Chun,et al.  Comparative metabolic and lipidomic profiling of human breast cancer cells with different metastatic potentials , 2016, Oncotarget.

[49]  Y. Fujiwara Cyclic phosphatidic acid - a unique bioactive phospholipid. , 2008, Biochimica et biophysica acta.

[50]  S. Ambs,et al.  Metabolic signatures of human breast cancer , 2015, Molecular & cellular oncology.

[51]  D. Im,et al.  Action and Signaling of Lysophosphatidylethanolamine in MDA-MB-231 Breast Cancer Cells , 2014, Biomolecules & therapeutics.

[52]  C A Halterman,et al.  Controlling quality. , 1982, Quintessence of dental technology.

[53]  C. Clarke,et al.  Metabolomic and proteomic analysis of breast cancer patient samples suggests that glutamate and 12-HETE in combination with CA15-3 may be useful biomarkers reflecting tumour burden , 2014, Metabolomics.

[54]  Lian‐Wen Qi,et al.  Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer , 2016, Oncotarget.

[55]  M. Gross,et al.  Quantification of diacylglycerol molecular species in biological samples by electrospray ionization mass spectrometry after one-step derivatization. , 2007, Analytical chemistry.

[56]  Yan Xu,et al.  Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction. , 2002, Biochimica et Biophysica Acta.

[57]  Andrew D. Southam,et al.  Monitoring cancer prognosis, diagnosis and treatment efficacy using metabolomics and lipidomics , 2016, Metabolomics.

[58]  C. Barbas,et al.  Metabolomic approach with LC-MS reveals significant effect of pressure on diver's plasma. , 2010, Journal of proteome research.

[59]  R. Clarke,et al.  Application of Metabolomics in Drug Resistant Breast Cancer Research , 2015, Metabolites.

[60]  Zhili Li,et al.  In situ characterizing membrane lipid phenotype of breast cancer cells using mass spectrometry profiling , 2015, Scientific Reports.

[61]  Feng Zhang,et al.  Dysregulated lipid metabolism in cancer. , 2012, World journal of biological chemistry.

[62]  P. Querzoli,et al.  Phospholipase C-beta 2 promotes mitosis and migration of human breast cancer-derived cells. , 2007, Carcinogenesis.

[63]  S. Narod,et al.  Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from medellín, Colombia , 2014, Hereditary Cancer in Clinical Practice.

[64]  Y. Nishizuka Protein kinase C and lipid signaling for sustained cellular responses , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[65]  C. McCulloch,et al.  Associations between breast cancer, plasma triglycerides, and cholesterol. , 1991, Nutrition and cancer.

[66]  M. Spraul,et al.  Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. , 2014, Analytical chemistry.

[67]  Coral Barbas,et al.  Gas chromatography-mass spectrometry (GC-MS)-based metabolomics. , 2011, Methods in molecular biology.

[68]  C. Townsend,et al.  Synthesis and antitumor activity of an inhibitor of fatty acid synthase , 2000 .

[69]  P. Domingues,et al.  Lipidomic analysis of phospholipids from human mammary epithelial and breast cancer cell lines , 2013, Journal of cellular physiology.

[70]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[71]  B. Faubert,et al.  Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. , 2011, Genes & development.

[72]  M. King,et al.  BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. , 2001, Human molecular genetics.

[73]  S. Sethi,et al.  Recent advances in lipidomics: Analytical and clinical perspectives. , 2017, Prostaglandins & other lipid mediators.

[74]  G. Kong,et al.  Quantitative analysis of phosphatidylcholines and phosphatidylethanolamines in urine of patients with breast cancer by nanoflow liquid chromatography/tandem mass spectrometry , 2009, Analytical and bioanalytical chemistry.

[75]  P. Maini,et al.  Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer , 2007, British Journal of Cancer.

[76]  C. Barbas,et al.  Metabolomics in cancer biomarker discovery: current trends and future perspectives. , 2014, Journal of pharmaceutical and biomedical analysis.

[77]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[78]  Jose M. Silva,et al.  Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy , 2002, Oncogene.

[79]  M. Mourtada-Maarabouni,et al.  Inhibition of Human T-Cell Proliferation by Mammalian Target of Rapamycin (mTOR) Antagonists Requires Noncoding RNA Growth-Arrest-Specific Transcript 5 (GAS5) , 2010, Molecular Pharmacology.

[80]  Arnald Alonso,et al.  Analytical Methods in Untargeted Metabolomics: State of the Art in 2015 , 2015, Front. Bioeng. Biotechnol..

[81]  B. El-Gamal,et al.  Serum lipids and tissue DNA content in Egyptian female breast cancer patients. , 2003, Japanese journal of clinical oncology.

[82]  Coral Barbas,et al.  Controlling the quality of metabolomics data: new strategies to get the best out of the QC sample , 2015, Metabolomics.

[83]  T. Powles,et al.  Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized 31P measurements of response to treatment , 1998, NMR in biomedicine.

[84]  I. Wilson,et al.  Evaluation of the repeatability of ultra-performance liquid chromatography-TOF-MS for global metabolic profiling of human urine samples. , 2008, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[85]  F. Podo Tumour phospholipid metabolism , 1999, NMR in biomedicine.

[86]  D. Wishart Emerging applications of metabolomics in drug discovery and precision medicine , 2016, Nature Reviews Drug Discovery.

[87]  D. Rose,et al.  Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. , 1998, International journal of oncology.

[88]  A. Molinari,et al.  Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells , 2012, Breast Cancer Research.

[89]  U. Hamann,et al.  High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia , 2007, Breast Cancer Research and Treatment.

[90]  Daniel Raftery,et al.  Early detection of recurrent breast cancer using metabolite profiling. , 2010, Cancer research.

[91]  C. Zielinski,et al.  Increased serum concentrations of cholesterol and triglycerides in the progression of breast cancer , 2004, Journal of Cancer Research and Clinical Oncology.

[92]  Peiyuan Yin,et al.  Current state-of-the-art of nontargeted metabolomics based on liquid chromatography-mass spectrometry with special emphasis in clinical applications. , 2014, Journal of chromatography. A.

[93]  S. Choi,et al.  Lipid profiles for HER2-positive breast cancer. , 2013, Anticancer research.

[94]  Yu Bai,et al.  Comprehensive lipid profiling of plasma in patients with benign breast tumor and breast cancer reveals novel biomarkers , 2015, Analytical and Bioanalytical Chemistry.

[95]  Z. Bhujwalla,et al.  Molecular Causes of the Aberrant Choline Phospholipid Metabolism in Breast Cancer , 2004, Cancer Research.

[96]  C. I. D. Vargas,et al.  Análisis de las mutaciones más frecuentes del gen BRCA1 (185delAG y 5382insC) en mujeres con cáncer de mama en Bucaramanga, Colombia , 2009 .

[97]  Hong-Shiee Lai,et al.  Plasma free amino acid profile in cancer patients. , 2005, Seminars in cancer biology.

[98]  U. Günther Metabolomics Biomarkers for Breast Cancer , 2015, Pathobiology.

[99]  D. Page,et al.  BRCA1 and BRCA2 hereditary breast carcinoma phenotypes , 1997 .

[100]  Debra L Winkeljohn Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[101]  J. Winnike,et al.  Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences. , 2016, Journal of proteome research.

[102]  S. Eckhardt,et al.  Clinical Applications of Metabolomics in Oncology: A Review , 2009, Clinical Cancer Research.

[103]  Stacy D. Sherrod,et al.  Untargeted Metabolomics Strategies—Challenges and Emerging Directions , 2016, Journal of The American Society for Mass Spectrometry.

[104]  Oliver Fiehn,et al.  Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue – a GC-TOFMS based metabolomics study , 2012, BMC Genomics.

[105]  Jie Chen,et al.  Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling , 2001, Science.

[106]  M. Spraul,et al.  750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. , 1995, Analytical chemistry.

[107]  Y. Mechref,et al.  Elevated levels of hydroxylated phosphocholine lipids in the blood serum of breast cancer patients. , 2009, Rapid communications in mass spectrometry : RCM.

[108]  Robert V Farese,et al.  Triglyceride accumulation protects against fatty acid-induced lipotoxicity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Jianguo Xia,et al.  Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst , 2011, Nature Protocols.

[110]  D. Noh,et al.  Overexpression of phospholipase D1 in human breast cancer tissues. , 2000, Cancer letters.

[111]  Tongshu Yang,et al.  Identification of possible biomarkers for breast cancer from free fatty acid profiles determined by GC-MS and multivariate statistical analysis. , 2012, Clinical biochemistry.

[112]  Y. Gong,et al.  Link between obesity and cancer: role of triglyceride/free fatty acid cycling. , 2014, European review for medical and pharmacological sciences.