Key Players in Choline Metabolic Reprograming in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC), defined as lack of estrogen and progesterone receptors in the absence of protein overexpression/gene amplification of human epidermal growth factor receptor 2, is still a clinical challenge despite progress in breast cancer care. 1H magnetic resonance spectroscopy allows identification and non-invasive monitoring of TNBC metabolic aberrations and elucidation of some key mechanisms underlying tumor progression. Thus, it has the potential to improve in vivo diagnosis and follow-up and also to identify new targets for treatment. Several studies have shown an altered phosphatidylcholine (PtdCho) metabolism in TNBCs, both in patients and in experimental models. Upregulation of choline kinase-alpha, an enzyme of the Kennedy pathway that phosphorylates free choline (Cho) to phosphocholine (PCho), is a major contributor to the increased PCho content detected in TNBCs. Phospholipase-mediated PtdCho headgroup hydrolysis also contributes to the build-up of a PCho pool in TNBC cells. The oncogene-driven PtdCho cycle appears to be fine tuned in TNBC cells in at least three ways: by modulating the choline import, by regulating the activity or expression of specific metabolic enzymes, and by contributing to the rewiring of the entire metabolic network. Thus, only by thoroughly dissecting these mechanisms, it will be possible to effectively translate this basic knowledge into further development and implementation of Cho-based imaging techniques and novel classes of therapeutics.

Early detection of changes in phospholipid metabolism during neoadjuvant chemotherapy in breast cancer patients using phosphorus magnetic resonance spectroscopy at 7T

“…In some of the metabolic ratios (PME/PDE and PME/Pi) a large variation among patients was observed, which is probably due to physiological differences in the heterogeneous patient group of our study including different kinds of tumors and different kinds of NAC treatment. It has been shown in several studies that estrogen and progesterone can be involved in activation of choline‐kinase . However, in this study no correlations were found among the metabolic ratios and ER status and PR status, which is probably due to the relatively low number of patients included.…”

“…It has been shown in several studies that estrogen and progesterone can be involved in activation of choline-kinase. 16,37 However, in this study no correlations were found among the metabolic ratios and ER status and PR status, which is probably due to the relatively low number of patients included. A larger patient population is required for a more FIGURE 5 PME/PDE measured after spectral fitting of the individual 31 P spectra before (blue) and after (red) the first cycle of NAC arranged for the different pathological responses.…”

Proton MR spectroscopy in the breast: Technical innovations and clinical applications

“…Further understanding of these metabolic mechanisms in TNBCs will improve the development and implementation of Cho-based imaging techniques and advance novel therapeutics. 84 The tCho integral value has been reported to be increased in human studies with well-differentiated tumor types with high proliferative activity. 57 Tumors with very low proliferative activity, especially lobular cancers, show a scarce choline fraction with the MRS spectra.…”

“…Several human and experimental studies have shown that phosphatidylcholine metabolism is altered in TNBCs and phosphocholine levels are increased in TNBCs. Further understanding of these metabolic mechanisms in TNBCs will improve the development and implementation of Cho‐based imaging techniques and advance novel therapeutics …”

Application of in vivo MR methods in the study of breast cancer metabolism

“…Differences in the metabolism between various breast tumor subtypes and the complex molecular mechanism of cell proliferation and molecular heterogeneity of breast lesions may account for such behavior . Iorio et al have documented altered PtdCho metabolism during TN breast cancer progression . Baik et al showed a statistically significant correlation of Cho concentration with the rate constant k ep from DCEMRI experiment, on the basis of Cho being associated with active cell replication while the tumor growth requires active angiogenesis, resulting in leaky immature vessels …”