# Understanding how elevated triglycerides contribute to triple negative breast cancer growth and metastasis

> **NIH NIH R37** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $523,192

## Abstract

Project Summary / Abstract
Despite significant advances in treatment, women are still dying from breast cancer, particularly triple negative
breast cancer (TNBC). More than 50% of women with TNBC have elevated circulating triglycerides (TGs), and
these elevated levels are associated with reduced breast cancer survival. While the link between
hypertriglyceridemia (HTG) and TNBC is well described in epidemiology studies, checking and treating TG levels
in women with TNBCs are not part of standard clinical care. To understand the biological links between HTG
and TNBC progression, we employ pre-clinical models of hypertriglyceridemia in isolation from other metabolic
abnormalities. In our preliminary studies, we have found that the mice with HTG develop more rapid growth and
metastasis in murine models of TNBC. The HTG mice demonstrated lipid profiles with elevated very low density
lipoprotein (VLDL), and high circulating of phospholipids associated with elevated VLDL. Examining RNA
sequencing gene expression, we found that a number of genes associated with cholesterol synthesis and
peroxisome proliferator activated receptor (PPAR) signaling were downregulated in the TNBC from our HTG
models, while cytoskeleton related genes were upregulated. As these gene expression changes have previously
been related to hypoxia signatures, we examined lipid peroxidation products and found higher levels of lipid
peroxidation sterols in the tumors from the HTG mice. In addition, we found increased phosphorylation of p42/44
mitogen activated protein kinase (MAPK) and epithelial to mesenchymal transition (EMT) markers. VLDL binds
to the VLDL receptor (VLDLR), which is part of a breast cancer gene signature that is associated hypoxia and is
highly expressed on the basal-like subtype of TNBC. High VLDLR expression in breast cancer has been
associated with cancer metastasis, and its expression in basal-like TNBC is associated with a 50% decrease in
recurrence free survival. Therefore, we hypothesized that HTG promotes TNBC growth and progression by
increased VLDL uptake through the VLDLR, which contributes to lipid peroxidation in hypoxic tumors. We
hypothesize that lipid peroxidation increases cell signaling which enhances tumor survival in the setting of
hypoxia, and also contributes to EMT, cytoskeletal changes and changes in the tumor immune
microenvironment. In this project we will explore the importance of tumor VLDLR expression in HTG-driven
TNBC growth and metastasis using patient derived xenografts. Secondly, we will examine the importance of an
abundant lipid peroxidation product in TNBC. Finally, we will explore therapeutic strategies to lower TG, which if
successful could readily be translated into clinical care to improve outcomes for women with HTG and TNBC.

## Key facts

- **NIH application ID:** 10522185
- **Project number:** 1R37CA266853-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Emily Jane Gallagher
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $523,192
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522185

## Citation

> US National Institutes of Health, RePORTER application 10522185, Understanding how elevated triglycerides contribute to triple negative breast cancer growth and metastasis (1R37CA266853-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522185. Licensed CC0.

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