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