Breast Cancer Research and Treatment

, Volume 146, Issue 1, pp 51–62

Cholesterol biosynthesis inhibitors as potent novel anti-cancer agents: suppression of hormone-dependent breast cancer by the oxidosqualene cyclase inhibitor RO 48-8071

  • Yayun Liang
  • Cynthia Besch-Williford
  • Johannes D. Aebi
  • Benford Mafuvadze
  • Matthew T. Cook
  • Xiaoqin Zou
  • Salman M. Hyder
Preclinical study

DOI: 10.1007/s10549-014-2996-5

Cite this article as:
Liang, Y., Besch-Williford, C., Aebi, J.D. et al. Breast Cancer Res Treat (2014) 146: 51. doi:10.1007/s10549-014-2996-5

Abstract

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.

Keywords

Breast cancer Tumor progression Cholesterol biosynthesis inhibitors Estrogen receptor 

Abbreviations

E

Estrogen

ER

Estrogen receptor

PR

Progesterone receptor

OSC

Oxidosqualene cyclase

RO

RO 48-8071 ([4′-[6-(Allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate])

FBS

Fetal bovine serum

SRB

Sulforhodamine B

PI

Propidium iodide

sc

Subcutaneous

iv

Intravenous

PBS

Phosphate-buffered saline

TBS-T

Tris-buffered saline containing 0.1 % Tween 20

ANOVA

Analysis of variance

SE

Standard error

DPN

2,3-bis(4-Hydroxyphenyl)-propionitrile

PHTPP

4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol

FACS

Fluorescence-activated cell sorting

Supplementary material

10549_2014_2996_MOESM1_ESM.tif (127 kb)
Supplementary material 1 (TIFF 127 kb)
10549_2014_2996_MOESM2_ESM.tif (52 kb)
Supplementary material 2 (TIFF 52 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yayun Liang
    • 1
    • 2
  • Cynthia Besch-Williford
    • 3
  • Johannes D. Aebi
    • 4
  • Benford Mafuvadze
    • 1
    • 2
  • Matthew T. Cook
    • 1
    • 2
  • Xiaoqin Zou
    • 1
    • 5
  • Salman M. Hyder
    • 1
    • 2
  1. 1.Dalton Cardiovascular Research CenterUniversity of MissouriColumbiaUSA
  2. 2.Department of Biomedical SciencesUniversity of MissouriColumbiaUSA
  3. 3.IDDEX RADILColumbiaUSA
  4. 4.Small Molecule Research, Medicinal Chemistry, Pharma Research & Early Development (pRED)F. Hoffmann-La Roche AGBaselSwitzerland
  5. 5.Department of Physics and Astronomy, Department of Biochemistry, and Informatics InstituteUniversity of MissouriColumbiaUSA

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