High cholesterol fuels cancer by promoting resistance to form of cell death

In a study published online Aug. 24 in the journal Nature Communication, a research team led by the Duke Cancer Institute identified the mechanisms at work, describing how breast cancer cells use cholesterol to develop stress tolerance, making them impervious to death as they migrate from the tumor site original.

“Most cancer cells die trying to metastasize – it’s a very stressful process,” said lead 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 who don’t die have this ability to overcome the cell’s stress-induced death mechanism. We have found that cholesterol is an integral part of this ability.”

McDonnell and his colleagues built on previous research conducted in their lab focusing on the link between high cholesterol and estrogen-positive breast and gynecologic cancers. These studies found that cancers fueled by the hormone estrogen benefited from cholesterol derivatives that act like estrogen, fueling cancer growth.

But a paradox has emerged for estrogen-negative breast cancers. These cancers are not estrogen-dependent, but high cholesterol is always associated with more serious disease, suggesting that a different mechanism may be at work.

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

But in the motive what doesn’t kill you makes you stronger, those who live emerge with a superpower that makes them able to resist ferroptosis, a natural process in which cells succumb to stress. These stress-resistant cancer cells then proliferate and metastasize easily.

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

“Unraveling this path has highlighted new approaches that may be useful for the treatment of advanced disease,” McDonnell said. “There are contemporary therapies in development that inhibit the pathway we have described. Importantly, these results once again underscore why lowering cholesterol – either by using drugs or by changing the diet – is a good idea for better health. “

In addition to McDonnell, the study’s authors include Wen Liu, Rachid Safi, Dmitri Kazmi, Binita Chakraborty, and Ching-yi Chang.

The study received financial support from the Breast Cancer Research Program of the Department of Defense and the National Institutes of Health.

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Materials provided by Duke University Medical Center. Note: Content can be changed for style and length.