# Investigating the role of CRAT as a driver of triple negative breast cancer chemoresistance

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

Project Summary/Abstract
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype in which limited targeted
therapies are available. Therefore, the standard of care treatment for TNBC patients is neoadjuvant
chemotherapy where ~50% of patients have residual tumor burden and poor prognosis after treatment.
Recently, it has been demonstrated that mitochondrial oxidative phosphorylation (oxphos) is both upregulated
and a therapeutic vulnerability in chemoresistant TNBC, however, the mechanism behind this finding is not
understood. The tricarboxylic acid cycle (TCA), which produces reducing equivalents necessary for oxphos, is
requires the molecule acetyl-CoA (AcCoA). AcCoA can be derived from the breakdown of long chain fatty
acids during fatty acid oxidation (FAO). Because heightened fatty acid metabolism has been associated with
improved survival in TNBC, it is possible that chemoresistant TNBC derives AcCoA from fatty acids, fueling the
TCA and oxphos. The gene carnitine acetyl transferase (CRAT) produces an enzyme (CrAT) that catalyzes the
reversible transfer of an acetyl group between CoA and carnitine within the mitochondria. It is thought that
CrAT buffers the pool of free AcCoA to maximize the energetic needs of the TCA cycle and to prevent pyruvate
dehydrogenase inhibition via excess AcCoA. Within chemoresistant TNBC, greater transcription and/or
translation of CRAT may maximize TCA-derived reducing equivalents needed for oxphos, aiding in
chemoresistance. We have identified the fatty acid metabolism pathway and CRAT as significantly enriched in
chemotherapy (docetaxel combined with carboplatin, standard NACT for TNBC)-resistant versus chemo-
sensitive TNBC PDXs and patient biopsies (NCT02547987) at the RNA and protein levels. In a preliminary
analysis of post-versus pre-NACT TNBC patient derived xenograft (PDX) tumors, I also found increased
cytosolic lipid droplets (LDs) in carboplatin treated PDXs compared to vehicle by transmission electron
microscopy (TEM), suggestive of enhanced fatty acid metabolism. Therefore, I hypothesize that elevated
expression of CRAT in chemoresistant TNBC provides enhanced metabolic plasticity, buffering lipid
derived accumulation of AcCoA to maximize TCA cycle flux and oxphos, aiding in chemoresistance. I
will address this hypothesis by determining if AcCoA is preferentially derived from increased fatty acid
oxidation in chemoresistant TNBC. I will investigate if CRAT ablation impairs chemosensitivity and survival
using both in vitro and in vivo models. I will also determine which isoform of CRAT is necessary and sufficient
to drive chemoresistance. Together, these studies will improve our mechanistic understanding of increased
oxphos in residual TNBC and provide rationale for therapies targeting CrAT function to improve prognosis for
chemoresistant patients.

## Key facts

- **NIH application ID:** 10536077
- **Project number:** 1F31CA275397-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Katherine Ellen Pendleton
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-08-03 → 2025-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536077

## Citation

> US National Institutes of Health, RePORTER application 10536077, Investigating the role of CRAT as a driver of triple negative breast cancer chemoresistance (1F31CA275397-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10536077. Licensed CC0.

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