Hormone-Independent Mouse Mammary Adenocarcinomas with Different Metastatic Potential Exhibit Different Metabolic Signatures

Daniela Bispo,Victoria Fabris,Luisa A Helguero,Claudia Lanari,Ana M Gil,Caroline A Lamb

doi:10.3390/biom10091242

Abstract

The metabolic characteristics of metastatic and non-metastatic breast carcinomas remain poorly studied. In this work, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was used to compare two medroxyprogesterone acetate (MPA)-induced mammary carcinomas lines with different metastatic abilities. Different metabolic signatures distinguished the non-metastatic (59-2-HI) and the metastatic (C7-2-HI) lines, with glucose, amino acid metabolism, nucleotide metabolism and lipid metabolism as the major affected pathways. Non-metastatic tumours appeared to be characterised by: (a) reduced glycolysis and tricarboxylic acid cycle (TCA) activities, possibly resulting in slower NADH biosynthesis and reduced mitochondrial transport chain activity and ATP synthesis; (b) glutamate accumulation possibly related to reduced glutathione activity and reduced mTORC1 activity; and (c) a clear shift to lower phosphoscholine/glycerophosphocholine ratios and sphingomyelin levels. Within each tumour line, metabolic profiles also differed significantly between tumours (i.e., mice). Metastatic tumours exhibited marked inter-tumour changes in polar compounds, some suggesting different glycolytic capacities. Such tumours also showed larger intra-tumour variations in metabolites involved in nucleotide and cholesterol/fatty acid metabolism, in tandem with less changes in TCA and phospholipid metabolism, compared to non-metastatic tumours. This study shows the valuable contribution of untargeted NMR metabolomics to characterise tumour metabolism, thus opening enticing opportunities to find metabolic markers related to metastatic ability in endocrine breast cancer.

Highlights

Breast cancer (BC) is the leading cause of cancer deaths among women, accounting for an estimated 15% of all cancer deaths worldwide in 2018 [1]
We suggest that metastatic HI tumours may be characterised by less changes in tricarboxylic acid cycle (TCA) and phospholipid metabolism and a different pattern comprising products of nucleotide and cholesterol and fatty acids (FA) metabolism
Putative interpretation of metabolomic results suggest that, compared to non-metastatic tumours, metastatic tumours seem to be characterised by relatively enhanced glycolysis and TCA activity, possibly resulting in faster NADH production and, higher mitochondrial transport chain activity and ATP synthesis, along with a lesser need for lipids β-oxidation

Summary

Introduction

Breast cancer (BC) is the leading cause of cancer deaths among women, accounting for an estimated 15% of all cancer deaths worldwide in 2018 [1]. Besides recognising major molecular subtypes, provide additional prognostic value, while giving insight into BC heterogeneity [2,3]. These approaches cannot, fully explain tumour metabolic characteristics [4]. Metabolomics has been used to evaluate inter-tumour (inter-individual) heterogeneity, either in an attempt to correlate metabolic profiles of human breast tumours with histological features or immunohistochemical markers [10,11,12,13], or to help distinguish intrinsic molecular subtypes in murine BC models [14,15,16]. Some studies have already suggested possible breast tumour subtyping schemes based on metabolic profiling [17,18]

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