High Cholesterol Fuels

Topic: High Cholesterol Fuels Cancer Metastasis by Fostering Resistance to a Form of Cell Death

Chronically high cholesterol levels are associated with increased risk of breast cancer, and with worse outcomes in most cancers, but the link hasn’t been fully understood. Studies in cancer cells and in mice by a Duke Cancer Institute-led team have now identified a mechanism that underpins how breast cancer cells use cholesterol to develop tolerance to stress, making them invulnerable as they migrate from the original tumor site. The findings showed that chronic exposure to the cholesterol metabolite, 27HC, effectively selects for cells that exhibit increased cellular uptake and/or biosynthesis of lipids, and these cells show much greater metastatic capacity. The results also showed that the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death.

“Most cancer cells die as they try to metastasize—it’s a very stressful process,” said Donald P. McDonnell, PhD, professor in the departments of pharmacology and cancer biology and medicine at Duke University School of Medicine. “The few that don’t die have this ability to overcome the cell’s stress-induced death mechanism. We found that cholesterol was integral in fueling this ability … Unraveling this pathway has highlighted new approaches that may be useful for the treatment of advanced disease. There are contemporary therapies under development that inhibit the pathway we’ve described.”

McDonnell is senior and corresponding author of the researchers’ published paper in Nature Communications, which is titled, “Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.”

Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types, and with poor outcomes in patients with existing disease, the authors explained. “Obesity, dysregulated lipid homeostasis, and other sequelae of the metabolic syndrome are associated with increased risk of breast cancer and with poorer outcomes in patients with established disease.”

In particular, they noted, there has been significant interest in identifying the impact of cholesterol on breast cancer pathogenesis, because hypercholesterolemia is a risk factor that could be modified by diet, and/or through the use of drugs. There is considerable evidence that hypercholesterolemia is an independent risk factor for breast cancer in postmenopausal women, the investigators stated. But while studies that have evaluated the use of statins (the most commonly used LDL-cholesterol-lowering drug) on breast cancer risk in postmenopausal women have yielded equivocal results, “more compelling,” the authors noted, are the results of some large studies that have demonstrated significant benefits, in terms of overall and disease-free survival, for patients taking a statin before or following a cancer diagnosis. “Understanding the different effects of hypercholesterolemia on disease incidence versus established disease will inform the development of new approaches to modify this axis for maximal therapeutic benefit,” the researcher stated.

Topic Discussed: High Cholesterol Fuels Cancer Metastasis by Fostering Resistance to a Form of Cell Death

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