New insights into cholesterol-mediated ERRα activation in breast cancer progression and pro-tumoral microenvironment orchestration.

Brindisi, M; Frattaruolo, L; Fiorillo, M; Dolce, V; Sotgia, F; Lisanti, MP; Cappello, AR

Abstract

Breast cancer remains the greatest cause of cancer-related death in women worldwide. Its aggressiveness and progression derive from intricate processes that occur simultaneously both within the tumour itself and in the neighbouring cells that make up its microenvironment. The aim of the present work was firstly to study how elevated cholesterol levels increase tumour aggressiveness. Herein, we demonstrate that cholesterol, by activating ERRα pathway, promotes epithelium-mesenchymal transition (EMT) in breast cancer cells (MCF-7 and MDA-MB-231) as well as the release of pro-inflammatory factors able to orchestrate the tumour microenvironment. A further objective of this work was to study the close symbiosis between tumour cells and the microenvironment. Our results allow us to highlight, for the first time, that breast cancer cells exposed to high cholesterol levels promote (a) greater macrophages infiltration with induction of an M2 phenotype, (b) angiogenesis and endothelial branching, as well as (c) a cancer-associated fibroblasts (CAFs) phenotype. The effects observed could be due to direct activation of the ERRα pathway by high cholesterol levels, since the simultaneous inhibition of this pathway subverts such effects. Overall, these findings enable us to identify the cholesterol-ERRα synergy as an interesting target for breast cancer treatment. [Abstract copyright: © 2022 Federation of European Biochemical Societies.]

Citation

Brindisi, M., Frattaruolo, L., Fiorillo, M., Dolce, V., Sotgia, F., Lisanti, M., & Cappello, A. (2022). New insights into cholesterol-mediated ERRα activation in breast cancer progression and pro-tumoral microenvironment orchestration. FEBS Journal, https://doi.org/10.1111/febs.16651

• Journal Article Type: Article
• Acceptance Date: Oct 12, 2022
• Publication Date: Oct 13, 2022
• Deposit Date: Nov 16, 2022
• Publicly Available Date: Oct 14, 2023
• Journal: The FEBS journal
• Print ISSN: 1742-464X
• Electronic ISSN: 1742-4658
• Publisher: Wiley
• DOI: https://doi.org/10.1111/febs.16651
• Keywords: ERRα, EMT, cholesterol, tumour microenvironment, cancer aggressiveness
• Publisher URL: https://doi.org/10.1111/febs.16651
• Additional Information: Additional Information : This is the accepted version of the following article: Brindisi, M., Frattaruolo, L., Fiorillo, M., Dolce, V., Sotgia, F., Lisanti, M.P. and Cappello, A.R. (2022), New insights into cholesterol-mediated ERRα activation in breast cancer progression and pro-tumoral microenvironment orchestration. FEBS J. https://doi.org/10.1111/febs.16651, which has been published in final form at https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.16651; Funders : Regione Calabria; Projects : PAC CALABRIA 2014-2020-Asse Prioritario 12, Azione