A Role for ER-Beta in the Effects of Low-Density Lipoprotein Cholesterol and 27-Hydroxycholesterol on Breast Cancer Progression: Involvement of the IGF Signalling Pathway?

Reham M Mashat,Jeff M P Holly,Claire M Perks,Hanna A Zielinska

doi:10.3390/cells11010094

Reham M Mashat, Jeff M P Holly + Show 2 more

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https://doi.org/10.3390/cells11010094

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Journal: Cells	Publication Date: Dec 29, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Southmead Hospital

Abstract

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

Highlights

Introduction iationsBreast cancer is the most common cancer worldwide in women and the leading cause of death, accounting for almost one in four cancer cases [1]
We firstly confirmed the effects of low-density lipoprotein (LDL) (0–100 μg/mL) on cell proliferation in an either oestrogen (ER)-αpositive cell line, MCF-7, and established that it had similar effects on the proliferation of an ER-α-negative breast cancer cell line, MDA-MB-231
Western immunoblot analysis was performed to show the protein abundance of EMT markers, fibronectin, and vimentin, and their densitometric analyses were corrected in (I) MCF-7 and (J) MDAMB-231 after being dosed with 27OHC (0.1 μM) and LDL (80 μg/mL). p-values were determined by using one-way statistical analysis in GraphPad Prism: ANOVA test plus least significant difference (LSD) post-hoc test (* p < 0.05, ** p < 0.01, *** p < 0.001)

Summary

Introduction

Introduction iationsBreast cancer is the most common cancer worldwide in women and the leading cause of death, accounting for almost one in four cancer cases [1]. Obesity and high cholesterol levels have been established as having negative impacts on breast cancer mortality [2,3]. There are three main types of breast cancer, as determined by the types of receptors they possess: 70% of all breast cancer are hormone-receptor-positive, with either oestrogen (ER) or progesterone (PR) receptors; 15–20% are ERBB2 (HER2)-positive; and 15% have none of these receptors and are termed triple negative [4]. Of breast cancers, whilst around 60% of all breast tumours that do not express ER-α are positive for ER-β expression [5]. Nuclear ER-β and its variants are expressed in 44.4% of TNBCs [6]. Clinical studies have indicated that endocrine-targeted therapy for Licensee MDPI, Basel, Switzerland

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