Glycerophosphocholine (GPC) is a poorly understood biomarker in breast cancer

Abstract

Stewart et al. (1) recently reported that EDI3 is the glycerophosphodiesterase responsible for breaking down glycerophosphocholine (GPC) to choline and G3P in mammalian cells. The authors further claim that this is of relevance in breast cancer, as this disease, according to the authors, is associated with reduced levels of GPC and a low GPC/phosphocholine (PCho) ratio. By implication, inhibition of EDI3 could increase the concentration of GPC, restore a normal GPC/PCho ratio, and reduce metastatic potential. In our opinion, this hypothesis, which is based on studies of cultured breast cancer cells, does not take recent clinical findings into account. In a cohort of 156 patients, our group has found that estrogen receptor-negative breast cancer is associated with low PCho and high GPC concentrations (2). Furthermore, we have demonstrated that a basal-like patient-derived animal model had a remarkably high GPC/PCho ratio (3), which was corroborated by analysis of tumor tissue from patients with triple-negative breast cancer. These findings clearly indicate that the most aggressive breast cancer subtypes have higher GPC concentration than subtypes with a better prognosis. Furthermore, we have studied the role of GPC as a biomarker for response to therapy. In breast cancer biopsy specimens collected from patients receiving neoadjuvant chemotherapy, we have found that a favorable response to treatment, in fact, is associated with a reduction in GPC concentration during the course of treatment (4). Finally, we have shown that reduction in GPC concentration after neoadjuvant chemotherapy is associated with long-term survival in this patient group (5). In summary, high GPC concentration and a GPC/PCho ratio >1 is associated with aggressive subtypes of breast cancer. Furthermore, a reduction in GPC levels can be predictive of response to treatment. These findings are not consistent with the hypothesis that restoration of a high GPC/PCho ratio would be beneficial in breast cancer, which forms the basis for the work of Stewart et al. (1). The abnormal metabolism of breast cancer, not surprisingly, reflects the heterogeneity of the disease. The complex role of GPC remains poorly understood, but it has become increasingly clear that high, rather than low, GPC concentrations are associated with poor prognosis in breast cancer. Thus, in our opinion, the available body of data is not taken into account. Pursuing the findings in the article (1) can, of course, lead to discovery of novel drug targets. However, research based on a hypothesis that is not consistent with clinical findings may be considered a suboptimal approach for targeting the abnormal choline metabolism in breast cancer. Inhibition of EDI3 could surely have inhibitory effects on breast cancer cells, as interference with choline phospholipid metabolism repeatedly has been associated with such effects. We therefore await further progress from Stewart et al. in this field in great anticipation, and hope that further elucidation of GPC metabolism can lead to findings of new prognostic biomarkers or drug targets.