Researchers at Duke Medicine conclude that high cholesterol may make breast cancer worse when they found that a byproduct of cholesterol functions like the hormone estrogen, leading to increases in the growth and spread of breast cancer. Studies have previously shown the link between obesity and breast cancer, but the exact cause of the increased risk had not been identified.
"What we have now found is a molecule - not cholesterol itself, but an abundant metabolite of cholesterol called 27HC," said senior author Donald McDonnell, Ph.D., chair of the Department of Pharmacology and Cancer Biology at Duke, "that mimics the hormone estrogen and can independently drive the growth of breast cancer."
The research for the first time explains the link between high cholesterol and breast cancer, especially in post-menopausal women, and suggests that dietary changes or therapies to reduce cholesterol may also offer a simple, accessible way to reduce breast cancer risk.
One solution may be to prescribe anti-cholesterol drugs such as statins, which appear to decrease levels of this estrogen-like molecule in addition to their cholesterol-lowering effects.
Researchers set out to determine whether this estrogen activity was sufficient on its own to promote breast cancer growth and metastasis, and whether controlling it would have a converse effect. Using mouse models that are highly predictive of what occurs in humans, McDonnell and colleagues demonstrated the direct involvement of 27HC in breast tumor growth. They also noted that the activity of this cholesterol metabolite was inhibited when the animals were treated with antiestrogens or when supplementation of 27HC was stopped, as well as reduced aggressiveness of the cancer to spread to other organs.
Because the hormone estrogen feeds an estimated 75 percent of all breast cancers, and an earlier finding from McDonnell's lab determined that 27-hydroxycholesterol - or 27HC - behaved similarly to estrogen in animals, the studies were then substantiated using human breast cancer tissue. The test response in the human tissue showed a direct correlation between the aggressiveness of the tumor and an abundance of the enzyme that makes the 27HC molecule. They also noted that 27HC could be made in other places in the body and transported to the tumor.
Additional insights from the study lead researchers to conclude high cholesterol, and the estrogen-mimicking 27HC, may counteract some of the most common forms of breast cancer therapies.
"The worse the tumors, the more they have of the enzyme," said lead author Erik Nelson, Ph.D., a post-doctoral associate at Duke.
Increased 27HC exposure, Nelson says, may be associated with the development of resistance to the antiestrogen tamoxifen and a reduction in the effectiveness of aromatase inhibitors, which are among the most commonly used breast cancer therapeutics.
"In essence," McDonnell said, "the tumors have developed a mechanism to use a different source of fuel," rendering therapies to block or reduce estrogen ineffective.
McDonnell said the findings suggest there may be a simple way to reduce the risk of breast cancer by keeping cholesterol in check, either with statins or a healthy diet. Additionally, for women who have breast cancer and high cholesterol, taking statins may delay or prevent resistance to endocrine therapies such as tamoxifen or aromatase inhibitors.
The next steps for research include clinical studies to verify those potential outcomes, as well as studies to determine if 27HC plays a role in other cancers, McDonnell said.
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