A new study published in the November 29, 2013 edition of the journal Science, sheds new light on a woman’s risk of developing breast cancer. The study, for the first time, explains the reason behind the established relationship between high cholesterol and breast cancer — especially in obese women who have reached menopause.[1]
Researchers from Duke Cancer Institutein North Carolina found that a primary metabolite of cholesterol formed by CYP27A1, a molecule called 27-hydroxycholesterol or 27HC, acts as a hormone by functioning as a selective estrogen receptor modulator (SERM) which promotes tumor growth and metastasis in mouse models of mammary cancer. They noted that this metabolite also serves as a partial agonist for a potent estrogen receptor and the liver X receptor (LXRs).
Observations from an unrelated study show that the enzyme responsible for the conversion of cholesterol to 27HC (CYP27A1) is primarily expressed in macrophages. And because tumor infiltrating macrophages are associated with more aggressive tumors and worse patient outcome, data suggests that 27HC, acting as either a circulating hormone or as a paracrine factor produced by macrophages, is a mechanistic link between hypercholesterolemia and breast cancer incidence. [2]
Furthermore, the reserachers noted that the most aggressive human breast cancers were found to express the highest level of the enzyme that converts cholesterol to 27HC, the researchers conclude that 27HC produced within tumors – in addition to circulating 27HC – may contribute to tumorigenesis, spurring the growth and spread of the most common breast cancer in mice, and perhaps in some women. [3]
…We have …found a molecule, not cholesterol itself, but an abundant metabolite of cholesterol, that mimics the hormone estrogen and can independently drive the growth of breast cancer…
Benefit of statins
The researchers also found that patients taking anti-cholesterol drugs such lipophilic inhibitors of 2-hydroxy-3-methylglutaryl coenzyme A (statins), demonstrate lower breast cancer incidence, and decreased breast cancer recurrence and thus appear to diminish the effect of this estrogen-like molecule. Although these findings are early, using mouse models and tumor cells, the study 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,” explained 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, that mimics the hormone estrogen and can independently drive the growth of breast cancer.”
The hormone estrogen feeds an estimated 75% of all breast cancers. In a key earlier finding from McDonnell’s lab, researchers determined that 27-hydroxycholesterol 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.[1]
Aggressive tumors
The study, funded by the National Institutes of Health and the Department of Defense, was 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.
Important and significant findings
“The worse the tumors, the more they have of the enzyme,” noted 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 the treatments of breast cancer.
“This is a very significant finding,” McDonnell noted. “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 explains that these 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 [brand names: Novaldex and Soltamox] or aromatase inhibitors.Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.[1]
“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 concluders.
For more information:
[1] Nelson ER, Wardell1 SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, et al. 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology. Science. 2013 Nov 29; 342 (6162): 1094-1098. DOI: 10.1126/science.1241908 [Article]
[2] Nelson ER, Wardell SE, Howe MK, Carver N, Umetani M, McDonnell DP. 27-Hydroxycholesterol, a Macrophage Synthesized Cholesterol Metabolite, as a Link Between Hypercholesterolemia and Breast Cancer Pathophysiology Endocr Rev, 2013; 34 (03_MeetingAbstracts): OR16-1 [Article]
[3] Kaiser J. Cholesterol Forges Link Between Obesity and Breast CancerScience 2013 Nov 29; 342 (6162) 1028. DOI: 10.1126/science.342.6162.1028 [Article]
Photo:Cells treated with the cholesterol metabolite 27HC. Photo courtesy: Duke Medicine.
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