Choline metabolites as diagnostic and therapeutic response indicators for breast cancer

Abstract

Choline metabolites are elevated in breast cancer, decrease in response to effective therapy and are detected non-invasively by magnetic resonance modalities. Decreases in choline metabolites occur early-on after initiation of treatment. There is potential for use of choline metabolites as non-invasive diagnostic and therapeutic response indicators. Choline metabolites are detected in vivo by magnetic resonance spectroscopy (MRS) in broad resonances which are composites of multiple compounds. Tumor extract studies have suggested that phosphocholine (PCho) is the component of these resonances with the greatest potential for use as a diagnostic marker or therapeutic response indicator. Since other compounds present in these broad resonances vary in concentration with cancer progression and in response to therapy, changes in these other resonances can potentially diminish the overall signal or dampen the detectable therapeutic response. The ability to resolve and quantify PCho in vivo increases the sensitivity of this detection method, and hence, increases its potential utility. Herein is reported the in vivo resolution and quantification of PCho in a human breast cancer xenograft model in mice. A significant PCho decrease is detected following treatment with the taxane docetaxel. This PCho decrease is correlated with the diffusion-weighted magnetic resonance imaging (DWMRI) measured increase in tumor water mobility, and with mitotic catastrophe, a non-apoptotic mode of cell death. By studying model system of human breast cancer cells, other metabolites in the choline pathway varying with cancer progression are determined, and the transcriptional expression of genes in the choline pathway is quantified. From these data and enzyme activity data reported by other groups, a model is proposed where a number of metabolic perturbations combine to elevate PCho in breast cancer. These perturbations include the elevation of choline transporter, choline kinase, and phospholipase activities, in combination with decreased CTP:PCho cytidylyltransferase (CCT) activity. By changes in metabolites and gene expression following therapy, it is proposed that increased CCT activity combined with decreased phospholipase and GPC phosphodiesterase activity lead to decreased PCho. In addition, expression of a putative choline transporter (CTL1 variant A) and a putative choline kinase (CHKL) is quantified in human breast cells.