High cholesterol fuels cancer by fostering resistance to a form of cell death

24 Aug 2021
High cholesterol fuels cancer by fostering resistance to a form of cell death

Chronically high cholesterol levels are known to be associated with increased risks of breast cancer and worse outcomes in most cancers, but the link has not been fully understood.

In a study appearing online in the journal Nature Communications, a research team led by the Duke Cancer Institute has identified the mechanisms at work, describing how breast cancer cells use cholesterol to develop tolerance to stress, making them impervious to death as they migrate from the original tumor site.

“Most cancer cells die as they try to metastasise, it’s a very stressful process,” said senior author Donald P. McDonnell, Ph.D., 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 fuelling this ability.”

McDonnell and colleagues built on earlier research in their lab focusing on the link between high cholesterol and oestrogen-positive breast and gynaecological cancers. Those studies found that cancers fuelled by the oestrogen hormone benefitted from derivatives of cholesterol that act like oestrogen, stoking cancer growth.

But a paradox emerged for oestrogen-negative breast cancers. These cancers are not dependent on oestrogens, but high cholesterol is still associated with worse disease, suggesting a different mechanism might be at work.

In the current study using cancer cell lines and mouse models, the Duke researchers found that migrating cancer cells gobble cholesterol in response to stress. Most die.

But in the what-doesn’t-kill-you-makes-you-stronger motif, those that live emerge with a super-power that makes them able to withstand ferroptosis, a natural process in which cells succumb to stress. These stress-impervious cancer cells then proliferate and readily metastasise.

The process appears to be used not only by ER-negative breast cancer cells, but other types of tumours, including melanoma. And the mechanisms identified could be targeted by therapies.

“Unraveling this pathway has highlighted new approaches that may be useful for the treatment of advanced disease,” McDonnell said.

“There are contemporary therapies under development that inhibit the pathway we’ve described. Importantly, these findings yet again highlight why lowering cholesterol, either using drugs or by dietary modification, is a good idea for better health.”

Source: Duke University Medical Center