ArticleWorld journal of stem cells2026
Hypoxia facilitates triple-negative breast cancer stem cells enrichment and stemness maintenance through oxidized ataxia telangiectasia mutated-induced one-carbon metabolism.
Article in World journal of stem cells, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCancer stem cells (CSCs) drive recurrence and therapeutic resistance in triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype. Intratumoral hypoxia, a common feature of solid tumors, promotes CSCs enrichment, yet the mechanisms sustaining CSCs stemness remain poorly understood. Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasia mutated (ATM) kinase (oxidized ATM, p-ATM) independently of DNA breaks.
aimTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBC-CSC stemness through c-Myc-mediated regulation of one-carbon metabolism.
methodsHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia. CSC stemness was assessed by mammosphere assays and flow cytometry. ATM activity was assessed by pharmacological inhibition (Ku60019) and short hairpin RNA knockdown. c-Myc binding to serine hydroxymethyltransferase 2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) promoters was analyzed by dual-luciferase reporter assays and chromatin immunoprecipitation. NADPH/NADP+ ratios were quantified, and metabolic reprogramming was profiled by liquid chromatography-tandem mass spectrometry metabolomics.
resultsHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells, as reflected by higher numbers of mammospheres (Hs578T: 214 ± 18; MDA-MB-231: 198 ± 16; both
conclusionHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation of MTHFD2 and SHMT2, linking hypoxia, redox signaling, and one-carbon metabolism. These findings suggest a potential therapeutic axis that could be exploited for TNBC treatment.
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