Transcriptomic and Metabolomic Differentiation of Breast Cancers: Progression and Therapy Response via Magnetic Resonance Spectroscopy and Quantitative Expression Profiling in the Choline pathway

Tumor choline metabolites have potential for use as diagnostic indicators of breast cancer progression and can be non-invasively monitored in vivo by magnetic resonance spectroscopy. Both a 31 P MR visible phosphomonoester peak (~3.9 ppm) and a total choline metabolite peak (~3.2 ppm) detected by 1 H MRS are elevated in human breast tumors. As determined by tumor extract studies, the principle diagnostic component of these peaks is phosphocholine (PCho), the biosynthetic precursor to the membrane phospholipid, phosphatidylcholine (PtdCho). In extracts of human breast cells, PCho and the PtdCho breakdown product, glycerophosphocholine, are incrementally increased in cell lines of increasing metastatic potential. The ability to resolve and quantify PCho in vivo would improve the precision of this putative diagnostic tool. Additionally, determining the biochemical mechanisms underlying these metabolic perturbations will improve the understanding of metastatic cancer and could suggest potential molecular targets for drug development. Reported herein is the in vivo resolution and quantification of PCho in a breast cancer xenograft model in SCID mice via image-guided 31 P MR spectroscopy, localized to small voxels. Also reported is the quantification of cytosolic and lipid metabolites in breast cancer cells of increasing cancer progression, and the identification of metabolites that differ amongst cell lines by degree of cancer aggressiveness. These metabolic differences are correlated with differences in expression of genes of the choline metabolic pathway. Gene expression changes following taxane therapy are also correlated with previously reported changes in choline metabolites following the same therapy in the same tumor model. Biochemical models explaining the metabolic changes are discussed.