The cholesterol metabolite 27-hydroxycholesterol can trigger the growth and metastasis of breast tumors in postmenopausal women, according to a study reported in Science.
Evidence linking metabolic syndrome with cancer has been building steadily, but the underlying mechanisms remain poorly understood. New findings recently reported in Science implicate a cholesterol metabolite, 27-hydroxycholesterol (27HC), in the growth and metastasis of breast tumors in postmenopausal women.
“The findings suggest that strategies aimed at lowering 27HC may have utility in the treatment and prevention of breast cancer,” says lead author Donald McDonnell, PhD, a professor of medicine at Duke University School of Medicine in Durham, NC.
The investigation was launched after McDonnell's lab generated two complementary findings. First, they showed that diets high in fat and cholesterol boost tumor growth in mice bred to express estrogen receptor (ER)–positive breast tumors. Second, they showed that 27HC activates the ER in mouse breast cancer cells. These findings led them to wonder whether it was 27HC or cholesterol itself that increased tumor growth rates.
To find out, the researchers bred mice expressing ER-positive breast tumors with mice that can't produce 27HC because the enzyme that generates the metabolite from cholesterol, known as CYP27A1, is knocked out. Tumor growth rates in the offspring were delayed by roughly 50 days. Conversely, tumor latency was shortened and tumor growth rates were accelerated in a different group of mice that can't degrade 27HC. Taken together, McDonnell explains, those findings implicate 27HC, rather than cholesterol per se, as the tumorigenic molecule.
“The 50-day increase in tumor latency in the CYP27A1 knockout mice is one of the most dramatic phenotypes I've ever seen,” he says.
Working with humanized mouse models for ER-positive breast cancer, the researchers then showed that blocking CYP27A1 expression inhibits the conversion of cholesterol to 27HC. Also in the humanized mouse models, they showed that high CYP27A1 levels in both cancer cells and tumor-associated macrophages correlate with high-grade malignancies and vice versa. That tumor-associated macrophages express CYP27A1 and produce their own 27HC poses a challenge, McDonnell explains, because cholesterol-lowering statins work mainly in the liver. His team aims to determine how best to control 27HC production within tumors.
McDonnell's research team also showed that while 27HC boosts tumor growth upon ER binding, it drives breast cancer metastasis by binding to the liver X receptor (LXR). According to McDonnell, this suggests the overall findings are significant not just for ER-positive tumors, but also for tumors that express LXR. His lab is now investigating the spectrum of cancers that express LXR.
Peter Tontonoz, MD, PhD, a professor of pathology and laboratory medicine at the University of California, Los Angeles, who was not associated with the study, says the results “show how diet can lead to elevated levels of a cholesterol metabolite that activates the ER, which is always bad in the case of breast cancer.
“How to target 27HC directly remains a somewhat open question,” he adds, “but the idea itself is provocative.”