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

> **NIH NIH SC2** · HERBERT H. LEHMAN COLLEGE · 2021 · $152,930

## Abstract

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.

## Key facts

- **NIH application ID:** 10267720
- **Project number:** 5SC2GM139676-02
- **Recipient organization:** HERBERT H. LEHMAN COLLEGE
- **Principal Investigator:** Columba de la Parra
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $152,930
- **Award type:** 5
- **Project period:** 2020-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267720

## Citation

> US National Institutes of Health, RePORTER application 10267720, Regulation of breast cancer cell metabolism by an alternate cap-dependent mechanism of translation initiation. (5SC2GM139676-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10267720. Licensed CC0.

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