Breast cancer cells express
enzymes that convert
cholesterol, the synthetic precursor of
steroid hormones, into
estrogens and
androgens, which then drive
breast cancer cell proliferation. In the present study, we sought to determine whether
oxidosqualene cyclase (OSC), an
enzyme in the
cholesterol biosynthetic pathway, may be targeted to suppress progression of
breast cancer cells. In previous studies, we showed that the OSC inhibitor RO 48-8071 (RO) may be a
ligand which could potentially be used to control the progression of
estrogen receptor-α (ERα)-positive
breast cancer cells. Herein, we showed, by real-time PCR analysis of
mRNA from human
breast cancer biopsies, no significant differences in OSC expression at various stages of disease, or between
tumor and normal mammary cells. Since the growth of
hormone-responsive
tumors is ERα-dependent, we conducted experiments to determine whether RO affects ERα. Using mammalian cells engineered to express human ERα or ERβ
protein, together with an ER-responsive
luciferase promoter, we found that RO dose-dependently inhibited 17β-estradiol (E2)-induced ERα responsive
luciferase activity (IC50 value, ~10 µM), under conditions that were non-toxic to the cells. RO was less effective against ERβ-induced
luciferase activity.
Androgen receptor (AR) mediated transcriptional activity was also reduced by RO. Notably, while ERα activity was reduced by
atorvastatin, the
HMG-CoA reductase inhibitor did not influence AR activity, showing that RO possesses broader antitumor properties. Treatment of human BT-474
breast cancer cells with RO reduced levels of
estrogen-induced PR
protein, confirming that RO blocks ERα activity in
tumor cells. Our findings demonstrate that an important means by which RO suppresses
hormone-dependent growth of
breast cancer cells is through its ability to arrest the
biological activity of ERα. This warrants further investigation of RO as a potential therapeutic agent for use against
hormone-dependent breast
cancers.