Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer

Abstract

Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype. BRCA1 promoter hypermethylation and the BRCAness phenotype of BC cell lines were also studied. The purpose of this study was to determine the metabolic signature of HBOC syndrome and TNBC patients and to evaluate the potential contribution of the metabolites identified to the genetic diagnosis of breast cancer. The present results show the existence of a differential metabolic signature for BC cells based on the BRCA1 functionality. None of the studied BC cell lines presented hypermethylation of the BRCA1 promoter region. We provide evidence of the existence of free methylated nucleotides capable of distinguishing plasma samples from HBOC patients as BRCA1-mutated and BRCA1 non-mutated, suggesting that they might be considered as BRCA1-like biomarkers for TNBC and HBOC syndrome.

Breast Cancer and BRCA1 and BRCA2 Pathogenic Variants

“…Breast cancer metabolomics is an area of growing interest. A recent study was able to determine a differential metabolic signature based on BRCA1 functionality [58] and may provide future biomarkers.…”

Recent advances in metabolomics of triple negative breast cancer

“…Analysis of the data from these highresolution methods provides a powerful platform for translational and clinical research and diagnostic applications. 10,11 Targeted metabolomic analysis determines concentrations of a limited and predefined subset of a few metabolites or pathway, whereas untargeted analyses is a global approach. 12 has significant effect on TNBC invasion.…”

“…20,21 TNBC has similarity with BRCA1 mutation-associated tumors, metabolic profiling of TNBC and hereditary breast and ovarian cancer using non-targeted liquid chromatography coupled to mass spectrometry technology analysis revealed that differential BRCA1 functionality may be used as differential metabolic signature BRCA1-like biomarkers for TNBC and HBOC syndrome. 10,22 Metabolomics studies have revealed that TNBC expresses high and glutathione peroxidase (GPx), glutathione, reducing equivalents (NADPH), and transcription factor Nrf2. 25 Elevated expression of ROS is associated with cancers due deregulated metabolic activity, loss of mitochondria and peroxisome activity, activation of an oncogene, and increased expression of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphorylase.…”

“…Figure describes various stages involved in metabolomics analysis ranging from sample collection, data acquisition, data analysis, and biological interpretation based on metabolite identified. Analysis of the data from these high‐resolution methods provides a powerful platform for translational and clinical research and diagnostic applications . Targeted metabolomic analysis determines concentrations of a limited and pre‐defined subset of a few metabolites or pathway, whereas untargeted analyses is a global approach …”

“…Carbon dots (CDs)‐based drug delivery system are used to evaluate the real‐time monitoring of endothelium and the penetrability into MCTS with a high spatio‐temporal resolution . TNBC has similarity with BRCA1 mutation‐associated tumors, metabolic profiling of TNBC and hereditary breast and ovarian cancer using non‐targeted liquid chromatography coupled to mass spectrometry technology analysis revealed that differential BRCA1 functionality may be used as differential metabolic signature BRCA1‐like biomarkers for TNBC and HBOC syndrome …”