Abstract Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by rapid progression, metabolic reprogramming, and limited therapeutic options. Under stress conditions such as nutrient deprivation or oxidative stress, TNBC cells suppress canonical translation initiation and rely on alternative mechanisms to maintain the production of stress-adaptive proteins. Death-Associated Protein 5 (DAP5), a member of the eIF4G family, facilitates an alternate cap-dependent translation under conditions in which canonical translation is inhibited. Our data suggest that DAP5 plays a critical role in orchestrating metabolic adaptation for TNBC progression and metastasis. To investigate the role of DAP5 in metabolic and oxidative stress adaptation, we used the well-characterized TNBC cell line MDA-MB-231 with either control or DAP5 silencing. We found that DAP5 activity persists under oxidative stress when canonical translation is suppressed, enabling sustained expression of glycolytic enzymes and supporting glycolytic flux. DAP5 silencing resulted in reduced translation of glycolytic proteins, including GLUT1 and hexokinase II. It also decreased proteins related to redox response singling pathways, including CDK12. Metabolomic profiling following DAP5 depletion indicated significant alterations in nucleotide cofactors and disruptions in metabolic pathways commonly enriched in metastatic cancers, including amino acid and glucose metabolism. Consistently, ATP assay measurement showed a significant reduction upon DAP5 silencing, suggesting impaired energy metabolism in TNBC cells. Our findings support a model in which DAP5-mediated translation preserves a subset of metabolic mRNAs critical for metastasis when translation is attenuated. DAP5 acts as a key regulator of TNBC metabolism by selectively translating metabolic mRNAs, particularly those involved in glucose metabolism, thereby sustaining stress adaptation and promoting metastatic behavior. Citation Format: Emilia F. Carlo, Columba de la Parra, Erna Mitaishvili, Blessing Ukandu. Regulation of metabolic and stress adaptation in triple-negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2029.
Carlo et al. (Fri,) studied this question.