Abstract 435: A key regulatory role of the translation initiation factor DAP5 in the metabolic reprogramming of metastatic breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, accounting for 10-15% of all breast cancers in women. The frequency of metastasis in TNBC is disproportionally high compared to other subtypes of breast cancer and is the primary cause of patient mortality. At the cellular level, TNBC's aggressive nature demands rapid adaptation of the tumor cells to navigate cellular stressors for survival and metastatic transformation. These survival adaptations include a cancer cell’s ability to reprogram its metabolism and regulate mRNA translation control, coordinating alternative pathways to retain a selective proteome and metabolites that will aid in survival, proliferation, and migration. Advanced cancers, including TNBC, are generally highly glycolytic, and have lower rates of mitochondrial respiration (OXPHOS), a phenomenon known as the Warburg effect. This metabolic shift prioritizes the generation of essential metabolic intermediates, to facilitate the production of cellular biomass and fuel proliferation. Another notable alternative pathway is mediated by the ubiquitously expressed translation initiation factor, Death Associated Protein 5 (DAP5). DAP5 is a homolog of eIF4G and mediates translation independently of the canonical mTORC1/eIF4E pathway. Our findings suggest that this alternative translation initiation plays a crucial role in regulating the metabolic reprogramming of metastatic breast cancer. This non-canonical pathway via DAP5 facilitates the selective translation of 20-30% cap-dependent mRNAs, many of which are essential in cancer cell survival, migration, and metabolism. Importantly, it has recently been shown that DAP5 is critical for breast cancer metastasis but not in primary tumor development. Furthermore, TNBC patient data shows that elevated levels of DAP5 mRNA are correlated with poor survival and metastasis. Our data, using the highly metastatic TNBC cell line, MDA-MB-231, demonstrated that silencing DAP5 significantly reduced glycolytic rate and glycolytic capacity. Consistent with these findings, translatome profiling, showed that DAP5 silencing reduced numerous metabolic targets including glycolytic enzymes and metabolite transporters. Calcium (Ca2+) signaling, which has an important role in cancer progression, migration, and cellular bioenergetics is also affected by DAP5 in TNBC cells. Collectively, our findings indicate that breast cancer cells utilize the translation initiation factor DAP5 to selectively translate mRNAs that support metabolic reprogramming and cell migration, suggesting that DAP5 has a key regulatory role in the cancer’s transformation. Citation Format: Erna Mitaishvili, Guilherme Henrique Souza Bomfim, Anna Zou, Moira Sauane, Rodrigo Lacruz, Columba de la Parra. A key regulatory role of the translation initiation factor DAP5 in the metabolic reprogramming of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 435.