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Cholesterol Inhibitor Blocks Breast Cancer Growth in Mouse Model

By BiotechDaily International staff writers
Posted on 02 Jul 2014
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Image: Space-filling model of the cholesterol molecule (Photo courtesy of Wikimedia Commons).
Image: Space-filling model of the cholesterol molecule (Photo courtesy of Wikimedia Commons).
A low molecular weight drug that inhibits cholesterol biosynthesis was found to block the growth of breast tumors by modifying the ratio of proliferative and antiproliferative estrogen receptors.

Investigators at the University of Missouri (Columbia, USA) used breast cancer cell cultures for in vitro studies and BT-474 breast tumor xenografts in nude mice for in vivo studies of tumor progression. They treated these animals with the drug RO 48-8071, a small-molecule inhibitor of oxidosqualene cyclase (OSC, a key enzyme in cholesterol biosynthesis).

Results published in the July 2014 issue of the journal Breast Cancer Research and Treatment revealed that in vitro exposure of estrogen receptor (ER)-positive human breast cancer cells to pharmacological levels of RO 48-8071 reduced cell viability. Administration of RO 48-8071 to mice with BT-474 tumor xenografts prevented tumor growth, with no apparent toxicity.

At the molecular level it was determined that RO 48-8071 degraded the proliferative alpha estrogen receptor (ERalpha) while concomitantly inducing the antiproliferative protein ERbeta. Chemical inhibition or genetic knockdown of ERbeta prevented RO 48-8071-induced loss of cell viability. Importantly, RO 48-8071 had no effect on the viability of normal human mammary cells.

“Cholesterol is a molecule found in all animal cells and serves as a structural component of cell membranes,” said senior author Dr. Salman Hyder, professor of biomedical sciences at the University of Missouri. “Because tumor cells grow rapidly they need to synthesize more cholesterol. Scientists working to cure breast cancer often seek out alternative targets that might slow or stop the progression of the disease, including the elimination of the cancerous cells. In our study, we targeted the production of cholesterol in cancer cells leading to death of breast cancer cells.”

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