# Nutrient Sensing and Transcriptional Regulation

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $391,980

## Abstract

SUMMARY Breast cancer is a heterogeneous disease consisting of several clinically and molecularly distinct
subtypes. Compared to other subtypes, Triple Negative Breast Cancer (TNBC), which represents 15-20% of all
breast cancer, occurs at a younger age and recurs more frequently with a reduced survival rate. Currently, no
targeted therapies are available for TNBC. Our short-term goal is to dissect the molecular pathways that
support TNBC growth and survival. Our long-term goal is to leverage these discoveries to identify novel targets
suitable for therapeutic development. We focus on how normal cells and cancer cells integrate intra- and
extracellular growth and nutrient signals to sustain growth and tumorigenesis. We are most interested in how
two members of the extended Myc network of transcription factors integrate growth and nutrient signals. c-Myc
and MondoA function in opposition to control the aggressive growth and survival of TNBC. In this application
we focus on the control of gene expression by MondoA and how metabolism shapes the MondoA-dependent
transcriptome in vitro and in vivo. MondoA is the principal regulator of glucose-dependent transcription with
Thioredoxin Interacting Protein (TXNIP) being its best-characterized direct and glucose-induced transcriptional
target. TXNIP has pleiotropic function. Best characterized among these many functions is one in fuel choice.
TXNIP is a potent suppressor of glucose uptake and aerobic glycolysis, but it can also drive the catabolism of
other fuels such as branched chain amino acids and ketones in mitochondria. Thus, high TXNIP levels drive
fuel oxidation in mitochondria, while restricting utilization of glucose. Conversely, low TXNIP levels tip fuel use
towards glucose and away from mitochondria. We have shown that several predominant oncogenes block
MondoA transcriptional activity, thereby decreasing TXNIP levels. This likely contributes to oncogene-
dependent aerobic glycolysis, i.e. the Warburg Effect, which is a common feature of cancer cells. We propose
to study how fuel choice controls MondoA transcriptional activity in vitro and in vivo and how signals from the
tumor microenvironment dictate MondoA transcriptional activity. In Aim 1, we will determine how TXNIP,
hypoxia and how the balance between glycolysis and oxidative phosphorylation controls MondoA
transcriptional activity. In Aim 2, we will determine whether MondoA is required for the establishment or
maintenance of tumorigenesis and whether MondoA is transcriptionally active in well perfused/oxygenated
tumor regions. To examine the generality of our findings, we will determine MondoA’s role in gene expression
and nutrient-sensing using other breast cancer cell lines and in conditionally reprogrammed breast cancer cells
from PDX models. In Aim 3, we will use genomics approaches to discover the direct MondoA-dependent
transcriptome in vivo and determine how these genes collaborate with MondoA to sustain TNBC
tumorigenesis. We wil...

## Key facts

- **NIH application ID:** 9932349
- **Project number:** 5R01CA222650-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Donald E Ayer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,980
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932349

## Citation

> US National Institutes of Health, RePORTER application 9932349, Nutrient Sensing and Transcriptional Regulation (5R01CA222650-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932349. Licensed CC0.

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