Concordant Release of Glycolysis Proteins into the Plasma Preceding a Diagnosis of ER+ Breast Cancer

Abstract

Although the identification of peripheral blood biomarkers would enhance early detection strategies for breast cancer, the discovery of protein markers has been challenging. In this study, we sought to identify coordinated changes in plasma proteins associated with breast cancer based on large scale quantitative mass spectrometry. We analyzed plasma samples collected up to 74 weeks prior to diagnosis from 420 ER+ cases and matched controls enrolled in the Women's Health Initiative cohort. A gene set enrichment analysis was applied to 467 quantified proteins linking their corresponding genes to particular biological pathways. Based upon differences in the concentration of individual proteins, glycolysis pathway proteins exhibited a statistically significant difference between cases and controls. In particular, the enrichment was observed among cases in which blood was drawn closer to diagnosis (effect size for the 0–38 weeks pre-diagnostic group: 1.91; p-value: 8.3E-05). Analysis of plasmas collected at the time of diagnosis from an independent set of cases and controls confirmed upregulated levels of glycolysis proteins among cases relative to controls. Together, our findings indicate that the concomitant release of glycolysis proteins into the plasma is a pathophysiological event that precedes a diagnosis of ER+ breast cancer.

Autoantibody Signatures Involving Glycolysis and Splicesome Proteins Precede a Diagnosis of Breast Cancer among Postmenopausal Women

“…We previously demonstrated progressively increased release of glycolysis proteins into the circulation in relation to time to diagnosis (18). We therefore examined the patterns of PKM2 levels in relation to time to diagnosis following blood collection and in relation to PKM2 autoantibodies in a separate set of samples from the WHI cohort.…”

“…A strong similarity with antigens associated with systemic lupus erythematosus and other autoimmune diseases, was noted among identified antigenic proteins in our breast cancer study. We have recently provided evidence of release into circulation of proteins associated with the glycolysis pathway in ER+ breast cancer plasmas prior to clinical diagnosis (18). We demonstrated increased release of glycolysis proteins with decreasing time-to-diagnosis after blood collection indicative of a positive correlation between circulating glycolysis protein levels and tumor growth.…”

“…Proteomic analysis demonstrated an increase in cancer-related immune complexes to glycolytic enzymes in newly diagnosed post-menopausal patients. The concurrent increase in circulating glycolysis protein levels (18) suggests formation of these complexes may explain the observed immune suppression. With a relatively low sensitivity, but high specificity, one could envision application of this signature to determine women that may be at higher risk of developing breast cancer within a year, thus compelling them to seek screening.…”

“…Arrays of lysate derived proteins allow delineation of immunogenic signatures involving natural proteins that may be subject to post-translational modification as previously applied to studies of lung(11–13), colon(14, 15), prostate(16) and pancreatic(17) cancers. We recently demonstrated that global profiling of the plasma proteome allows identification of sets of proteins progressively released into the circulation at a pre-clinical stage of breast tumor development that may be grouped into biological pathways (18). There is similarly a need to delineate sets of proteins associated with biological pathways and networks that elicit autoantibodies with breast tumor development.…”

Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

“…Amon et al identified increased levels of glycolysis proteins in plasmas of women with breast cancer [27]. Glycolysis for ATP synthesis rather than oxidative phosphorylation occurs primarily when cells are deprived of oxygen, but the Warburg hypothesis suggests the central role of glycolysis in cancer and tumor cells even in the presence of oxygen [28].…”