Health for life

A byproduct of cholesterol functions like the hormone estrogen to fuel the growth and spread of the most common types of breast cancers, researchers at the Duke Cancer Institute report.

The researchers also found that anti-cholesterol drugs such as statins appear to diminish the effect of this estrogen-like molecule.

Published in the Nov. 29, 2013, edition of the journal Science, the findings are early, using mouse models and tumor cells. But 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.

"A lot of studies have shown a connection between obesity and breast cancer, and specifically that elevated cholesterol is associated with breast cancer risk, but no mechanism has been identified," said senior author Donald McDonnell, Ph.D., chair of the Department of Pharmacology and Cancer Biology at Duke. "What we have now found is a molecule – not cholesterol itself, but an abundant metabolite of cholesterol – called 27HC that mimics the hormone estrogen and can independently drive the growth of breast cancer."

The hormone estrogen feeds an estimated 75 percent of all breast cancers. In a key earlier finding from McDonnells lab, researchers determined that 27-hydroxycholesterol – or 27HC – behaved similarly to estrogen in animals.

For their current work, the 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, as well as the aggressiveness of the cancer to spread to other organs. 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.

The studies were substantiated using human breast cancer tissue. An additional finding 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.

"The worse the tumors, the more they have of the enzyme," said lead author Erik Nelson, Ph.D., a post-doctoral associate at Duke. Nelson said gene expression studies revealed a potential association between 27HC exposure and the development of resistance to the antiestrogen tamoxifen. Their data also highlights how increased 27HC may reduce the effectiveness of aromatase inhibitors, which are among the most commonly used breast cancer therapeutics.

"This is a very significant finding," McDonnell said. "Human breast tumors, because they express this enzyme to make 27HC, are making an estrogen-like molecule that can promote the growth of the tumor. In essence, the tumors have developed a mechanism to use a different source of fuel."

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.

A lifelong diet rich in omega-3 fatty acids can inhibit growth of breast cancer tumours by 30 per cent, according to new research from the University of Guelph.

The study, published recently in the Journal of Nutritional Biochemistry, is believed to be the first to provide unequivocal evidence that omega-3s reduce cancer risk.

“It’s a significant finding,” said David Ma, a professor in Guelph’s Department of Human Health and Nutritional Sciences, and one of the study’s authors.

“We show that lifelong exposure to omega-3s has a beneficial role in disease prevention – in this case, breast cancer prevention. What’s important is that we have proven that omega-3s are the driving force and not something else.”

Breast cancer remains the most common form of cancer in women worldwide and is the second leading cause of female cancer deaths.

Advocates have long believed diet may significantly help in preventing cancer. But epidemiological and experimental studies to back up such claims have been lacking, and human studies have been inconsistent, Ma said.

“There are inherent challenges in conducting and measuring diet in such studies, and it has hindered our ability to firmly establish linkages between dietary nutrients and cancer risk,” he said.

“So we’ve used modern genetic tools to address a classic nutritional question.”

For their study, the researchers created a novel transgenic mouse that both produces omega-3 fatty acids and develops aggressive mammary tumours. The team compared those animals to mice genetically engineered only to develop the same tumours.

“This model provides a purely genetic approach to investigate the effects of lifelong omega-3s exposure on breast cancer development,” Ma said.

“To our knowledge, no such approach has been used previously to investigate the role of omega-3s and breast cancer.”

Mice producing omega-3s developed only two-thirds as many tumours – and tumours were also 30-per-cent smaller – as compared to the control mice.

“The difference can be solely attributed to the presence of omega-3s in the transgenic mice – that’s significant,” Ma said.

“The fact that a food nutrient can have a significant effect on tumour development and growth is remarkable and has considerable implications in breast cancer prevention.”

Known as an expert in how fats influence health and disease, Ma hopes the study leads to more research on using diet to reduce cancer risk and on the benefits of healthy living.

“Prevention is an area of growing importance. We are working to build a better planet, and that includes better lifestyle and diet,” he said.

“The long-term consequences of reducing disease incidence can have a tremendous effect on the health-care system.”