In most human breast
cancers,
tumor cell proliferation is
estrogen dependent. Although
hormone-responsive
tumors initially respond to anti-
estrogen therapies, most of them eventually develop resistance. Our goal was to identify alternative targets that might be regulated to control
breast cancer progression.
Sulforhodamine B assay was used to measure the viability of cultured human
breast cancer cell lines exposed to various inhibitors.
Protein expression in whole-
cell extracts was determined by Western blotting. BT-474
tumor xenografts in nude mice were used for in vivo studies of
tumor progression.
RO 48-8071 ([4'-[6-(Allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone
fumarate]; RO), a small-molecule inhibitor of
oxidosqualene cyclase (OSC, a key
enzyme in
cholesterol biosynthesis), potently reduced
breast cancer cell viability. In vitro exposure of
estrogen receptor (ER)-positive human
breast cancer cells to pharmacological levels of RO or a dose close to the IC50 for OSC (nM) reduced cell viability. Administration of RO to mice with BT-474
tumor xenografts prevented
tumor growth, with no apparent toxicity. RO degraded ERα while concomitantly inducing the anti-proliferative
protein ERβ. Two other
cholesterol-lowering drugs,
Fluvastatin and
Simvastatin, were less effective in reducing
breast cancer cell viability and were found not to induce ERβ. ERβ inhibition or knockdown prevented RO-dependent loss of cell viability. Importantly, RO had no effect on the viability of normal human mammary cells. RO is a potent inhibitor of
hormone-dependent human
breast cancer cell proliferation. The anti-
tumor properties of RO appear to be in part due to an off-target effect that increases the ratio of ERβ/ERα in
breast cancer cells.