Inborn-like errors of metabolism are determinants of breast cancer risk, clinical response and survival: a study of human biochemical individuality.

Ismael Da Silva ,Bruno Scarpellini,Irmgard Himmel,Renato Fraietta,Heidi Fiegl,Daniel Egle,Christina Troi,Clóvis Silva ,Rosa Paula M Biscolla ,Délcio Matos ,Dirce Maria Lobo Marchioni ,Edmund C Baracat ,Renato Tomioka ,Maria Izabel Chiamolera ,Celso R Silva ,Celso Granato ,Felipe C.g Reis ,André Lopes Carvalho ,Márcia Batista Salzgeber ,Iara Baldim Rabelo ,Antônio Augusto Ferreira Carioca ,Edson Guimarães Loturco ,Rui M B Maciel ,José Renato Assis Lemos Marques De Oliveira ,R S Díaz ,Paulo D’amora ,C Stella ,Carlos Augusto Rodrigues Véo ,Cristovam Scapulatempo Neto ,Rene Da Costa Vieira ,Gustavo Arantes Rosa Maciel ,Sandra Monteiro Silva ,Patrícia Eiko Yamakawa ,Marcelo A Mori ,Robert A Nagourney

doi:10.18632/oncotarget.25839

Abstract

Breast cancer remains a leading cause of morbidity and mortality worldwide yet methods for early detection remain elusive. We describe the discovery and validation of biochemical signatures measured by mass spectrometry, performed upon blood samples from patients and controls that accurately identify (>95%) the presence of clinical breast cancer. Targeted quantitative MS/MS conducted upon 1225 individuals, including patients with breast and other cancers, normal controls as well as individuals with a variety of metabolic disorders provide a biochemical phenotype that accurately identifies the presence of breast cancer and predicts response and survival following the administration of neoadjuvant chemotherapy. The metabolic changes identified are consistent with inborn-like errors of metabolism and define a continuum from normal controls to elevated risk to invasive breast cancer. Similar results were observed in other adenocarcinomas but were not found in squamous cell cancers or hematologic neoplasms. The findings describe a new early detection platform for breast cancer and support a role for pre-existing, inborn-like errors of metabolism in the process of breast carcinogenesis that may also extend to other glandular malignancies.Statement of Significance: Findings provide a powerful tool for early detection and the assessment of prognosis in breast cancer and define a novel concept of breast carcinogenesis that characterizes malignant transformation as the clinical manifestation of underlying metabolic insufficiencies.

Highlights

Breast cancer remains a leading cause of morbidity and mortality throughout the world [1, 2]
Validation was undertaken that compared 169 population-based control samples, against results obtained in 154 cases from an independent and earlier reported disease cohort the “Risk Prediction of Breast Cancer Metastasis Study” (Italy and Austria) (Supplementary Information) (Figure 1D–1L)
To examine the hypoglycemia premise, we developed an experimental murine model in which insulin was administered to mice under normo- and hypoglycemic conditions [19, 20]. In this murine model only the hypoglycemic mice that received insulin www.oncotarget.com www.oncotarget.com recapitulated the MYC-dependent shifts that had been observed in cancer patients, characterized by the insulin/ MYC-dependent reactions of i: glutaminolysis (Gln/Glu), (Ala/Glu) and [(Gln/Glu)/Asp] as well as glycolysis (Ser/ C2) and the combination of both (Ser/C2)/[(Gln/Glu)/Asp] ii: glutamate pulling effect (Glu/Hexoses) iii: arginine methyltransferase activity [Total DMA/[(Gln/Glu)/Asp] and [Tau/[(Gln/Glu)/Asp] iiii: liver function [branched-chain (Leu+Ile+Val) amino acids (BCAA)/ (Phe+Tyr)], ornithine decarboxylase activity (Spermidine), iiiiii: liver neoglucogenesis [Hexoses/(Ala+Gly+Ser)] and iiiiiii: peroxisomal impairment (Figure 5A–5J) (Red arrows). To confirm these findings in humans, we examined whether blood concentrations of hexoses correlated with peroxisome dysfunction, as represented by the elevation of specific lipids containing very long chain fatty acids (VLCFA)

Summary

Introduction

Breast cancer remains a leading cause of morbidity and mortality throughout the world [1, 2]. Earlier diagnosis through the application of mammography and magnetic resonance imaging has improved the detection of smaller volume disease providing physicians the opportunity to intervene at earlier stages when the cancers are most curable [3]. The advent of molecular technologies, widely applied in prognostic determinations, have evolved into diagnostic tools that utilize circulating tumors cells and cell free DNA for earlier detection, prognosis and where applicable response prediction. Numerous clinical trials are exploring the clinical utility of these approaches [4, 5]. Proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation [6]

Methods

Results

Conclusion