New research led by the Duke Cancer Institute has identified one of the ways cholesterol can enhance the ability of cancer cells to metastasize. The study focused particularly on breast cancer, shedding light on prior observational research linking statin use to better survival rates.
“Most cancer cells die as they try to metastasize – it’s a very stressful process,” explains Donald McDonnell, senior author on the newly published study. “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.”
Prior studies have found high levels of cholesterol can enhance tumor growth in estrogen-positive breast cancers. This finding was not necessarily a surprise, as certain metabolites of cholesterol have been known to act in ways similar to estrogen.
But researchers have also detected associations between high cholesterol and worse disease outcomes in patients with estrogen-negative breast cancers. So this new research set out to better understand what mechanism links cholesterol with cancer cells that are not sensitive to estrogen.
Using animal and cell models, the researchers zoomed in on what happens to cancer cells when they are exposed to 27-hydroxycholesterol (27HC), a metabolite of cholesterol. It was discovered that in response to high chronic levels of 27HC, cancer cells increase their uptake of lipids.
This triggers increases in an enzyme called GPX4 that protects the cell from damage caused by this increased lipid uptake. It also helps prevent a type of cell death called ferroptosis.
Resistance to ferroptosis has been found to be a key feature of metastatic cancer cells. So the hypothesis raised by this new research suggests high levels of cholesterol can increase the ability of cancer cells to resist ferroptotic cell death and subsequently heighten a patient’s risk of their cancer metastasizing.
“Unraveling this pathway has highlighted new approaches that may be useful for the treatment of advanced disease,” says McDonnell. “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.”
These findings will need to be confirmed in human subjects, but several prior observational studies have seen higher survival rates in breast cancer patients who are taking statins for high cholesterol. However, the researchers are unsure whether currently available statins are the best drugs to specifically target this newly discovered mechanism.
It may be likely blocking the metabolic conversion of cholesterol to 27HC is a more effective way to turn these findings into an effective cancer therapy. Other options proposed in the study point to GPX4 inhibitors reducing the ability of tumor cells to resist ferroptotic cell death.
“There are several GPX4 inhibitors in development although it remains to be determined if their therapeutic index will be good enough to permit their use in cancer patients,” the new study concludes.
The study was published in the journal Nature Communications.
Source: Duke Health