title: Molecular causes of the aberrant choline phospholipid metabolism in breast cancer.
abstract: Proton magnetic resonance spectroscopy ((1)H MRS) consistently detects significant differences in choline phospholipid metabolites of malignant versus benign breast lesions. It is critically important to understand the molecular causes underlying these metabolic differences, because this may identify novel targets for attack in cancer cells. In this study, differences in choline membrane metabolism were characterized in breast cancer cells and normal human mammary epithelial cells (HMECs) labeled with [1,2-(13)C]choline, using (1)H and (13)C magnetic resonance spectroscopy. Metabolic fluxes between membrane and water-soluble pool of choline-containing metabolites were assessed by exposing cells to [1,2-(13)C]choline for long and short periods of time to distinguish between catabolic and anabolic pathways in choline metabolism. Gene expression analysis using microarrays was performed to understand the molecular mechanisms underlying these changes. Breast cancer cells exhibited increased phosphocholine (PC; P < 0.001), total choline-containing metabolites (P < 0.01), and significantly decreased glycerophosphocholine (P < 0.05) compared with normal HMECs. Decreased (13)C-enrichment was detected in choline (P < 0.001) and phosphocholine (P < 0.05, P < 0.001) of breast cancer cells compared with HMECs, indicating a higher metabolic flux from membrane phosphatidylcholine to choline and phosphocholine in breast cancer cells. Choline kinase and phospholipase C were significantly overexpressed, and lysophospholipase 1, phospholipase A2, and phospholipase D were significantly underexpressed, in breast cancer cells compared with HMECs. The magnetic resonance spectroscopy data indicated that elevated phosphocholine in breast cancer cells was primarily attributable to increased choline kinase activity and increased catabolism mediated by increased phospholipase C activity. These observations were consistent with the overexpression of choline kinase and phospholipase C detected in the microarray analyses.
authors.affiliation: Magnetic Resonance Oncology Section, Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002247:Carbon Isotopes; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D010743:Phospholipids / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism; D011522:Protons
chemical_list: D002247:Carbon Isotopes; D010743:Phospholipids; D011522:Protons; D010767:Phosphorylcholine; D002797:Choline Kinase; D002794:Choline