Cholesterol-Lowering Treatment Blocks Epithelial-Mesenchymal Transition (EMT) Associated Invasiveness and Drug Resistance in Breast and Colorectal Adenocarcinoma Models

Q: What role does EMT play in cancer progression and metastasis?

EMT is a cellular process that enables cancer cells to invade and metastasize. It involves loss of epithelial characteristics and gain of mesenchymal traits, supporting migratory and invasive behavior.

Q: How was cholesterol-lowering tested in relation to EMT?

Cholesterol-lowering effects on EMT were evaluated using three cell line models and three EMT inducers. Compounds including MβCD, HPβCD, and simvastatin were used, with measurements of cholesterol-associated cellular components and EMT gene/protein expression.

Q: What were the main outcomes of HPβCD treatment after EMT induction?

Cholesterol depletion with HPβCD reversed EMT-associated expression patterns, reduced relative invasion in NMuMG cells, and lowered multidrug resistance measurements in MCF-7 cells.

Sep 22, 2026

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Epithelial-mesenchymal transition (EMT) drives invasion and metastasis, and deregulated cholesterol has been linked to treatment resistance and metastatic potential, yet the EMT–cholesterol connection remains unclear. Cholesterol-lowering was tested across breast and colorectal adenocarcinoma cell-line models using EMT inducers and cholesterol-modulatory compounds. HPβCD reduced free cholesterol, lipid rafts, and lipid droplets, reversed EMT-associated gene expression, and lowered invasion and multidrug resistance. The findings support cholesterol depletion as a potential therapeutic strategy to mitigate metastatic cancer progression.

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Introduction

Abstract

Cancer Medicine | RESEARCH ARTICLE OPEN ACCESS
Cholesterol-Lowering Treatment Blocks
Epithelial-Mesenchymal Transition (EMT) Associated Invasiveness and Drug Resistance in Breast and Colorectal Adenocarcinoma Models
Shanen Perumal | Naaziyah Abdulla | Ruth Aronson | Mandeep Kaur
School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
Correspondence: Mandeep Kaur ([mandeep.kaur@wits.ac.za](mandeep.kaur@wits.ac.za))
Received: 4 August 2025 | Revised: 28 January 2026 | Accepted: 18 June 2026
Keywords: cancer progression | cholesterol lowering | cyclodextrins | drug resistance | epithelial-mesenchymal transition | | | --- | --- | | ABSTRACT
Background: Epithelial-mesenchymal transition (EMT) is a cellular process involved in the invasion and metastasis of cancer cells. Deregulated cellular cholesterol is associated with treatment resistance and metastatic potential in cancer cells; however, the link between EMT and cholesterol is unclear.
Methods: We tested the effect of cholesterol-lowering on EMT using three cell line models and three EMT inducers. EMT was induced in NMuMG, MCF-7 and HT-29 cells to assess the effect of cholesterol-modulatory compounds, MβCD, HPβCD and simvastatin. Free cholesterol, lipid droplets and lipid rafts in cellular membranes were evaluated using immunofluorescence microscopy. Expression of EMT-associated genes was assessed using immunofluorescent staining, RT-qPCR and Western blotting. Results: Following cholesterol depletion (free cholesterol, lipid rafts and lipid droplets) with HPβCD, RT-qPCR showed an increase in CDH1 expression (log2 fold change [log2FC] = 2.03; p < 0.001), and a decrease in Vim (log2FC = −1.01; p < 0.05) in NMuMG cells post EMT. Expression of cholesterol biosynthesis gene HMGCR (log2FC = −1.72; p< 0.01), and efflux genes ABCA1 (log2FC = −1.74; p< 0.01) and ABCG1 (log2FC = −4.81; p< 0.001) were reduced. A 68.4%(p < 0.001) reduction in relative invasion in NMuMG cells and a 41.3%(p < 0.01) reduction in multidrug resistance measurements in MCF-7 cells were observed post-EMT after HPβCD treatment.
Conclusion: Cholesterol depletion reversed EMT-associated expression patterns in all three cell models. Results from this study support cholesterol depletion as a potential therapeutic intervention for mitigating metastatic cancer progression. | | | 1 | Introduction | occurs during embryonic development, wound healing and tissue regeneration. EMT can also drive cancer progression by | | Cancer is a leading cause of death worldwide, with rising inci- | enhancing the migratory and invasive properties of cells, en- | | dence and mortality rates that reflect the growth and ageing of | abling malignancy at distant organs [3] . Several different signal- | | the global population [1]. Metastasis accounts for approximately | ling pathways are involved in EMT-associated signalling, with | | 60.1% of cancer-related mortality, increasing to 66.7% when only | considerable cross-talk between signalling pathways, including | | considering solid tumours [2] . Epithelial-mesenchymal transi- | the TGFβ signal transduction pathway, hypoxia-induced sig- | | tion (EMT) is a reversible physiological process that normally | nalling with the concomitant expression of HIF-1α, and IL-6/ | | Shanen Perumal and Naaziyah Abdulla shared co-first Authors. | | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2026 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd. | | Cancer Medicine, 2026; 15:e72070 1 of 17 [https://doi.org/10.1002/cam4.72070](https://doi.org/10.1002/cam4.72070) JAK2/STAT3 activation [4–6] . These signalling pathways upregulate the expression of EMT-inducing transcrip

FAQs

What role does EMT play in cancer progression and metastasis?

EMT is a cellular process that enables cancer cells to invade and metastasize. It involves loss of epithelial characteristics and gain of mesenchymal traits, supporting migratory and invasive behavior.

How was cholesterol-lowering tested in relation to EMT?

Cholesterol-lowering effects on EMT were evaluated using three cell line models and three EMT inducers. Compounds including MβCD, HPβCD, and simvastatin were used, with measurements of cholesterol-associated cellular components and EMT gene/protein expression.

What were the main outcomes of HPβCD treatment after EMT induction?

Cholesterol depletion with HPβCD reversed EMT-associated expression patterns, reduced relative invasion in NMuMG cells, and lowered multidrug resistance measurements in MCF-7 cells.

Sep 22, 2026

Upload by Franzy