Abstract Background: Triple negative breast cancer (TNBC) is a highly aggressive subtype distinguished by the lack of hormone receptors and specific molecular targets, leading to limited treatment options, high recurrence rates, and poor clinical prognosis. The Warburg effect in cancer cells generates a tumor microenvironment characterized by hypoxia, low glucose, and high lactate, which severely promote chemo-resistance, immune escape, and distant metastasis. Nevertheless, prognostic significance of hypoxia and lactate metabolism-related genes in TNBC remains largely unclear, and more accurate prediction models are urgently needed. Methods: Clinical information and gene expression profiles of TNBC patients were obtained from the online database. LASSO and multivariate Cox regression analysis were used to establish the hypoxia and lactate metabolism-related prediction model, and prognostic value was further validated by Kaplan-Meier plotter, receiver operating characteristic curves, and nomogram. Gene set enrichment analysis was performed to evaluate the pathways and molecular functions of hypoxia and lactate metabolism-related gene signature. Tumor mutation, microsatellite instability, RNA expression-based stemness scores, immune infiltration, and drug susceptibility analysis were applied to identify potential therapeutic targets. A series of in vitro experiments were performed to evaluate the biological function of the selected gene. Results: Five genes including COL5A3, LRRC8D, IGFL1, SEPTIN3, and PEG10 were identified to establish the hypoxia and lactate metabolism-related risk score. TNBC patients divided into high-risk or low-risk group by risk score exhibited substantial differences in survival outcome, tumor mutation, immune infiltration, and drug sensitivity. Gene set enrichment analysis revealed that difference between these two groups may be related to extracellular matrix, intercellular links, intercellular information transfer, immune-related pathways, angiogenesis and metabolism. The constructed model showed strong predictive performance, with receiver operating characteristic curves showing area under the curve values of 0.82, 0.86, and 0.90 at 1, 3 and 5 years, respectively. In vitro studies indicated that hub gene COL5A3 could promote tumor proliferation, migration, and drug resistance via PI3K/AKT pathway in TNBC cells. Conclusion: A novel five hypoxia and lactate metabolism-related gene signature could be used for prognosis prediction in TNBC patients, and hub gene COL5A3 promotes TNBC progression via PI3K/AKT pathway. Further research is needed to explore the biological roles of these genes in TNBC aiming to refine therapeutic approaches. Citation Format: W. ChenQ. ShaoZ. WangB. Zhu. Hypoxia and lactate metabolism-relatedgene signature for prognosis prediction in triple negative breast cancerand hub gene COL5A3 promotes cancer progressionvia PI3K/AKT pathway abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-03-28.
Chen et al. (Tue,) studied this question.
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