Plasmalogen Deficiency and Overactive Fatty Acid Elongation Biomarkers in Serum of Breast Cancer Patients Pre- and Post-Surgery—New Insights on Diagnosis, Risk Assessment, and Disease Mechanisms

Abstract

The polyunsaturated fatty acid (PUFA) elongase, ELOVL5, is upregulated in breast cancer (BC) vs. adjacent normal tissue. We performed a comprehensive lipid metabolomic analysis of serum using high-resolution accurate mass spectrometry from two case-control studies that included non-BC, BC subjects pre-surgery, and BC subjects one-month post-surgery to determine if the metabolic signatures of over-active fatty acid elongation and other lipid changes could be detected in BC vs. non-BC subjects: study 1 (n = 48: non-BC, n = 69: pre-surgery BC); study 2 (blinded validation: n = 121: non-BC, n = 62: pre-surgery BC, n = 31: one month post-surgery). The ratio of the ELOVL5 precursor, linoleic acid (18:2) to a non-ELOVL5 precursor, oleic acid (18:1) was evaluated in multiple lipid pools (phosphatidylethanolamine (PtdEtn), phosphatidylcholine (PtdCho), lyso-PtdCho, and free fatty acids). This ratio was lower in pre-surgery BC subjects in all pools in both studies (p < 0.001). At one-month post-surgery, the 18:2/18:1 ratios increased vs. pre-surgery and were no longer different from non-BC subjects (p > 0.05 expect for lyso-PtdCho). In contrast to the elongation biomarkers, docosahexaenoic acid (22:6n-3) containing ethanolamine plasmalogen (EtnPls) species were observed to be further decreased in BC subjects one-month post-surgery vs. pre-surgery levels (p < 0.001). These results are consistent with the hypothesis that ELOVL5 is upregulated in BC tissue, which would result in the selective depletion of 18:2 vs. 18:1 containing lipid species. Surgical removal of the tumor removes the overactive ELOVL5 effect on serum lipids. In contrast, the low EtnPls levels do not appear to be caused by BC tumor activity and may be pre-existent and a possible risk factor for BC. These results indicate that it may be possible to screen for both breast cancer risk and breast cancer activity using a simple blood test.

Tumor Lipid Signatures Are Descriptive of Acquisition of Therapy Resistance in an Endocrine-Related Breast Cancer Mouse Model

“…Therefore, we hypothesize that PLs’ increases are needed to sustain tumor growth, both by enhancing membrane biosynthesis, including for endoplasmic reticulum capacity enhancement and particularly to support extended protein glycosylation . Hence, increased PL levels (namely, PtdCho, SMs, PtdEtn, and Pls, in decreasing order of abundance) are confirmed as differentiators of tumoral tissue from healthy tissue and of tumors of increasing aggressiveness, as reported in previous studies of BC. ,− However, to our knowledge, these changes were here observed for the first time as accompanying the HD to HI, and to HIR, transitions in the MPA mouse model of BC. Indeed, in HIR tumors, these increases are consistent with the lowest GPC levels previously reported for the same tumors (Figure ).…”

Prognostic implication and immunotherapy response prediction of a ubiquitination-related gene signature in breast cancer

“…There are diverse models for breast cancer, based on metabolic heterogeneity, stromal immune phenotype, diverse cell-death patterns, cell necroptosis, plasmalogen deficiency, overactive fatty acid elongation biomarkers, and 4-mRNA metastasis-related genes ( Xie et al, 2018 ; Zheng et al, 2020 ; Tomida et al, 2021 ; Yu et al, 2021 ; Xie et al, 2022 ; Zou et al, 2022 ). Yu et al demonstrated that energy-related metabolic features in BC were related to glycolytic activity and survival.…”

Baseline Elevations of Leukotriene Metabolites and Altered Plasmalogens Are Prognostic Biomarkers of Plaque Progression in Systemic Lupus Erythematosus

“…Plasmalogen levels are reduced in SLE patients and are correlated with increased oxidative stress ( 66 ). Nguma et al, have suggested that ethanolamine plasmalogens may even serve a protective role against oxidative stress and have studied the utility of these molecules in the treatment of colitis in murine models ( 67 ). Levels of several choline plasmalogens were found by Nishimukai et al to have a strong inverse correlation to progression of atherosclerosis and have even been suggested as possible biomarkers of CVD ( 68 ).…”