Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion

Sep 23, 2026

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Fibroblast growth factor receptor (FGFR) signaling is active in up to 85% of breast cancers and enhances tumor-cell proliferation, migration, and invasion. This study shows that FGFR activation regulates cholesterol metabolism by upregulating sterol O-acyltransferase 1 (SOAT1), driving cellular cholesterol storage. SOAT1 inhibition reduces FGFR-driven colony formation and invasion and aligns with decreased matrix metalloproteinase expression. Genetic SOAT1 knockdown diminishes mammary tumor growth in vivo, revealing a metabolic role and therapeutic vulnerability in FGFR-driven cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

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Abstract

Background

FGFR signaling in breast cancer and TNBC

Endocrine and metabolic FGFs in metabolism

Cholesterol roles and rationale

Tuokkola et al. Breast Cancer Research (2025) 27:132 [https://doi.org/10.1186/s13058-025-02084-9](https://doi.org/10.1186/s13058-025-02084-9) Breast Cancer Research RESEARCH Open Access Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion Jennifer E. Tuokkola 1, Lyndsay E. Reese2, Ying Wang2, Christine H. O’Connor2,3, Jillian G. VanTreeck 1, Annisa H. Rumahorbo2 and Kathryn L. Schwertfeger2,4,5* Abstract Signaling by fibroblast growth factor receptors (FGFRs) is active in up to 85% of breast cancers and results in enhanced proliferation, migration, and invasion of tumor cells. Here, we show that FGFR signaling regulates cholesterol metabolism in breast cancer. Specifically, we demonstrate that FGFR activation promotes cellular cholesterol storage by upregulating expression of the enzyme sterol O-acyltransferase 1 (SOAT1) . Moreover, we demonstrate that inhibition of SOAT1 attenuates FGFR-driven colony formation and invasion in tumor cells, which correlates with reduced expression of matrix metal loproteinase expression. Furthermore, genetic knockdown of SOAT1 decreases mammary tumor growth in vivo. Taken together, these findings suggest a largely undiscovered metabolic role for FGFR signaling in regulating cholesterol metabolism in breast cancer and present a therapeutic vulnerability that could be targeted in FGFR-driven cancers. Keywords Triple-negative breast cancer, Fibroblast growth factor, Cholesterol metabolism, Cholesterol storage *Correspondence: Kathryn L. Schwertfeger [schwe251@umn.edu](schwe251@umn.edu) 1Molecular Pharmacology and Therapeutics Graduate Program, University of Minnesota, Minneapolis, MN, USA 2Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA 3Supercomputing Institute, University of Minnesota, University of Minnesota, Minneapolis, MN, USA 4Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA 5Center for Immunology, University of Minnesota, Minneapolis, MN, USA Background Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in a wide range of biological processes including cell proliferation, survival, differentiation, and migration [1]. In breast cancer, signaling by the FGF/FGFR axis is associated with enhanced cellular proliferation, migration, survival, and angiogenesis [2, 3]. Amplification of the FGFR1 gene is observed in 10% of breast cancer patients and is associated with poor survival rates and increased therapeutic resistance [4, 5]. In triple-negative breast cancer (TNBC), FGFR1 amplification is seen in 9% of cases and is correlated with early relapse and poor survival in TNBC patients [6, 7]. Of the breast cancer subtypes, TNBC cell lines display the greatest sensitivity to FGFR inhibitors, indicating that © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Tuokkola et al. Brea

FAQs

How does FGFR signaling influence cholesterol metabolism in breast cancer cells?

FGFR activation promotes cellular cholesterol storage by upregulating SOAT1 expression, linking FGFR signaling to cholesterol metabolism in breast cancer.

What is the effect of inhibiting or knocking down SOAT1 on tumor cell behavior?

SOAT1 inhibition attenuates FGFR-driven colony formation and invasion, and genetic knockdown of SOAT1 decreases mammary tumor growth in vivo.

Why is the FGFR–SOAT1 axis considered a therapeutic vulnerability?

Because the findings reveal an undiscovered metabolic role for FGFR signaling in cholesterol metabolism and show that targeting SOAT1 can reduce invasive growth driven by FGFR activity.

Sep 23, 2026

Uploaded by Terk