Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells.

Samantha A. Hutchinson,Thomas A. Hughes,Priscilia Lianto,J. Bernadette Moore,James L. Thorne

doi:10.3390/ijms20133241

Samantha A. Hutchinson, Thomas A. Hughes + Show 3 more

Open Access

https://doi.org/10.3390/ijms20133241

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Abstract

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery.

Highlights

Overweight and obese breast cancer (BCa) patients [1,2], and those with associated co-morbidities such as elevated levels of low-density lipoprotein cholesterol (LDL-C) [3], or high saturated fat intake [4], have worse disease-free survival than their leaner counterparts
We selected a range of PSSs with similar structures and that are commonly consumed in the diet (STAN, sitosterol (Cat: 700095) (SITO), campesterol (Cat: 700126) (CAMP), brassicasterol (Cat: 700122) (BRAS), stigmasterol (Cat: 700062) (STIG))
CAMP impaired MDA-MB-231 viability at 100 nM and above, while STIG was effective at 1 μM and above, SITO and BRAS at 10 μM and 100 μM, and sitostanol (Cat: 700121) (STAN) at 100 μM only (Figure 2b)

Summary

Introduction

Overweight and obese breast cancer (BCa) patients [1,2], and those with associated co-morbidities such as elevated levels of low-density lipoprotein cholesterol (LDL-C) [3], or high saturated fat intake [4], have worse disease-free survival than their leaner counterparts. Plant-based diets [5], physically active lifestyles, or long-term pharmacological therapies [6,7] that lower LDL-C, are associated with reduced risk of primary and recurrent breast cancer, and improved patient survival. Biochemical modifications of the cholesterol backbone by members of the cytochrome P450 family produces a pool of signalling molecules termed oxysterols (Figure 1a), which allow local and systemic homeostatic control of cholesterol metabolism via their binding affinity for the liver X receptors alpha and beta (LXRA, LXRB) [8,9]. The oxysterol-LXR axis drives metastasis of breast tumours [11], and the concentrations of several oxysterols are altered in primary breast tumour tissue [12] and in the circulation of those who have relapsed compared to those with primary disease [13]

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