Androgen receptor-positive breast cancer, characterized by overexpression of androgen receptors (ARs), is attracting attention as a subcategory of triple-negative breast cancer (TNBC). The involvement of androgen signaling and the presence of endocrine activity in these TNBC cells make them potential treatment targets. Recent improvements in metabolomics measurement techniques have also revealed the metabolic characteristics of cancer cells. Different cancer cell subtypes exhibit different metabolic balances, and it is believed that a shift to aerobic glycolysis occurs in TNBC, although oxidative phosphorylation has been heavily implicated in endocrine-dependent breast cancer. In this study, we used metabolomics to investigate metabolic regulatory mechanisms in androgen receptor-positive TNBC.
We introduced ARs into the MDA-MB-231 strain of TNBC cells by using the pEGFP-C1-AR plasmid vector, establishing a stable AR-forced expression TNBC line (MDA-MB-231-AR). Positively ionized metabolites were purified from the parental cell line and the AR forced expression cell line. Metabolome analysis was conducted using a capillary electrophoresis–mass spectrometer (CE-TOFMS/-QqQMS). Data analysis was carried out by extracting, cross-checking, and ordering peaks using MasterHands.
Hierarchical clustering analysis of metabolite peak values showed that the MDA-MB-231-AR strain had improved biological malignancy compared to the parental strain. An evaluation of energy metabolism pathways (the glycolysis system, the pentose phosphate pathway, and tricarboxylic acid cycle) showed that the MDA-MB-231-AR strain had a higher NADH/NAD+ ratio and a lower lactic acid/pyruvic acid ratio than the parental strain, suggesting improved hypoxic metabolism. The glutathione/oxidized glutathione ratio was also lower in the MDA-MB-231-AR cell line than in the parental strain, indicating release from oxidative stress.
Improved hypoxic metabolism was observed in the energy metabolism pathways of AR-positive TNBC cells. This suggests a possible shift from aerobic glycolysis to oxidative phosphorylation might in TNBC cells.
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