Cholesterol byproduct encourages spread of breast cancer, metastasis

A diet high in cholesterol could be increasing the risk of metastasis in breast cancer patients, researchers at the University of Illinois recently reported in the journal Nature Communications.

Obesity is a well-established risk factor for the onset of breast cancer, lead study author Erik R. Nelson, PhD, and colleagues wrote, and the metabolic condition fuels poorer survival rates and recurrences in patients who already have the disease, so much so that more than 90 percent of all breast cancer mortality is attributable to metastasis. Contributing to the rise of obesity is what some scientists call the “Western diet”—one high in fats and cholesterol.

Researchers haven’t been able to identify the apparent link between high cholesterol levels and metastasizing in breast cancer patients until Nelson’s team found a culprit: a byproduct of cholesterol metabolism that preys on immune cells and manipulates them to encourage cancer growth instead of repair.

The cholesterol byproduct is called 27-hydroxycholesterol, or 27HC, and is produced by an enzyme involved in cholesterol metabolism. Using mice models to test the effect of high cholesterol on established tumors, Nelson and colleagues fed mice with established breast cancer diets high in cholesterol. The researchers noticed that, as predicted, tumor growth in the rodents, as well as metastasis, increased. Mice who were treated with cholesterol-lowering statins saw less metastasis.

The team manually inhibited the enzyme linked to 27HC in another group of mice and saw a suppressing effect in the animals—the breast cancer didn’t seem to metastasize.

Nelson and colleagues also noted that 27HC changed the function of immune cells at metastatic sites, urging T-cells and neutrophils to continue spreading cancer rather than eliminating the tumors.  

“We found that 27HC is not working on the cancer cells themselves, but it’s actually working on the immune cells, or white blood cells,” Nelson said in a University of Illinois YouTube video. “And what it does is it hijacks those cells and redirects them from fighting cancer to promoting cancer. So this allows the cancer to spread unchecked.”

After expanding their research beyond breast cancer, Nelson and co-authors found in an additional study that at other solid tumor sites, including those linked to colon cancer, lung cancer, melanoma and pancreatic cancer, 27HC had the same negative effect on tumor growth and metastasis. What this means, they wrote, is that developing a small-molecule drug aimed at inhibiting 27HC could result in an effective treatment for patients with several different types of cancer.

“We’re currently working with our clinical partners to determine whether the effects we see in mice also hold true in human tissue,” Nelson said. “The other thing that we’re currently working on is to develop better inhibitors of 27HC. We’re hopeful that our studies will lead to new therapeutic options for the treatment of patients with metastatic disease of breast cancer but also of other solid tumors.”