Regulation of breast cancer cell metabolism by an alternate cap-dependent mechanism of translation initiation.

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Project Summary/Abstract Translational control and metabolic reprogramming are hallmarks of advanced cancers. Many important genes involved in all aspects of cancer development and progression express mRNAs that are selectively translationally regulated, including regulators of cancer cell metabolism. Cancer cells acquire an altered metabolism, switching from oxidative phosphorylation (OXPHOS) to glycolytic phenotype (Warburg effect), to increase reliance on alternate metabolic pathways for production of amino acids, lipids, nucleic acids and energy in order to support growth, proliferation and metastasis. Triple-negative breast cancer (TNBC), one the most aggressive and highly metastatic subtypes of BC with the poorest outcome, is characterized by elevated glycolysis and low OXPHOS. TNBC models and patient samples are characterized by dysregulated glycolysis which is linked to chemotherapeutic resistance. Still, the exact mechanism by which this metabolic switch occurs is largely unknown. Using a TNBC cell model, it has been shown that an alternate mechanism of cap-dependent but mTORC1/eIF4E- independent mRNA translation via DAP5-eIF3d complexes modulates several mRNAs including those involved in glucose metabolism. This application proposes to study the important role of translational regulation of breast cancer cell metabolism by the DAP5/eIF3d complex. The central hypothesis is that DAP5/eIF3d is critical in regulating the switch from Ox-Phosphorylation to aerobic glycolysis, which are metabolic pathways essential for metastasis, the principal cause of death in breast and all types of cancer. In this SC2 proposal, the PI proposes to understand the important role of the DAP5-eIF3d complex in the translational regulation of key mRNAs involved in cancer cell metabolism of TNBC models. The central hypothesis will be tested by pursuing three specific aims: (1) Determine the role of DAP5/eIF3d in the metabolic switch from oxidative phosphorylation to aerobic glycolysis in well characterized TNBC cell lines; (2) Identify the molecular mechanism by which DAP5/eIF3d modulates the translation of mRNAs associated with cancer cell metabolism and (3) Utilize human primary tumor biopsies of metastasized TNBCs to validate DAP5/eIF3d targets and correlated with metabolic molecular biomarkers. The research proposed in this application is innovative, because it focuses on understanding a new mechanism of cap- dependent mRNA translation in the regulation of metastatic cancer cell metabolism. This is highly significant because the role of selective translation initiation in cancer metabolism is almost completely unexplored. Ultimately, such knowledge has the potential of identify a novel mechanism by which selective regulation of translation initiation drives TNBC metastasis and eventually will offer new opportunities for development innovative therapies to treat advanced breast cancer characterized by dysregulated metabolism.