# Crosstalk between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer

> **NIH NIH R37** · BAYLOR COLLEGE OF MEDICINE · 2021 · $362,569

## Abstract

ABSTRACT
It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However,
the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic
reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates
Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1α and its substrate XBP1 via multiple
mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple
negative breast cancer (TNBC) to IRE1α/XBP1 inhibition, possibly mediated via altered interorganelle
communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a
framework to seek biological insight into this altered communication between the ER, mitochondria, and
nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of
IRE1α as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We
hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1α, and its substrate XBP1, to promote
mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will
elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial
metabolic reprogramming in TNBC. In Aim 1, we will investigate the biological significance of IRE1α/XBP1
mediated ER-nucleus communication in MYC-driven TNBC. Aim 2 will determine the role of mitochondrial FAO
activation by the IRE1α/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy
and mechanisms of combination therapy with IRE1α inhibitor and docetaxel in treating MYC-driven TNBC. The
resulting data from this proposal will be significant as they will promote the development of novel, mechanism-
based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC-
driven TNBC.

## Key facts

- **NIH application ID:** 10180914
- **Project number:** 5R37CA228304-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xi Chen
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,569
- **Award type:** 5
- **Project period:** 2018-07-12 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180914

## Citation

> US National Institutes of Health, RePORTER application 10180914, Crosstalk between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer (5R37CA228304-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180914. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*