Metabolic markers of breast cancer: enhanced choline metabolism and reduced choline-ether-phospholipid synthesis.
Specific genetic alterations during malignant transformation may induce the synthesis and breakdown of choline phospholipids, mediating transduction of mitogenic signals. The high level of water-soluble choline metabolites in cancerous breast tumors, relative to benign lesions and normal breast tissue, has been used as a diagnostic marker of malignancy. To unravel the biochemical pathways underlying this phenomenon, we used tracer kinetics and 13C and 31P magnetic resonance spectroscopy to compare choline transport, routing, and metabolism to phospholipids in primary cultures of human mammary epithelial cells and in MCF7 human breast cancer cells. The rate of choline transport under physiological choline concentrations was 2-fold higher in the cancer cells. The phosphorylation of choline to phosphocholine and oxidation of choline to betaine yielded 10-fold higher levels of these metabolites in the cancer cells. However, additional incorporation of choline to phosphatidylcholine was similar in both cell types. Thus, enhanced choline transport and augmented synthesis of phosphocholine and betaine are dominant pathways responsible for the elevated presence of choline metabolites in cancerous breast tumors. Uniquely, reduced levels and synthesis of a choline-ether-phospholipid may also serve as a metabolic marker of breast cancer.
Katz-Brull
Rachel
R
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. rkatzbr@caregroup.harvard.edu
Seger
Dalia
D
Rivenson-Segal
Dalia
D
Rushkin
Edna
E
Degani
Hadassa
H
D001622:Betaine / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism*; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002247:Carbon Isotopes; D002794:Choline / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010742:Phospholipid Ethers / Q000378:metabolism*; D010743:Phospholipids / Q000096:biosynthesis*; D010758:Phosphorus; D010767:Phosphorylcholine / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002247:Carbon Isotopes; D026901:Membrane Transport Proteins; D010742:Phospholipid Ethers; D010743:Phospholipids; C065637:choline transporter; D010767:Phosphorylcholine; D010758:Phosphorus; D001622:Betaine; D002794:Choline