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?

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-alpha-positive and ER-alpha-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-alpha (ER-alpha)-positive breast cancer cells in an ER-alpha-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-alpha. Using ER-alpha-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor beta (ER-beta). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-alpha-positive breast cancer cells via ER-alpha, but migration and invasion are mediated via ER-beta in ER-alpha 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-beta 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-beta is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-beta in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

Automated summary

High levels of cholesterol, especially LDL and its metabolite 27-OHC, are associated with increased risks of breast cancer and obesity. This study found that LDL/27-OHC promotes cell proliferation in breast cancer cells through the activation of specific enzymes. The effects of 27-OHC on cell migration and invasion are dependent on ER-alpha in ER-alpha-positive cells and ER-beta in ER-alpha positive and negative cells. Cholesterol increases IGF-I production and IGF-IR abundance in TNBC, and targeting ER-beta may be an alternative approach to control the impact of LDL in breast cancer patients.