27-Hydroxycholesterol Promotes Some Breast Cancer Growth

Examining the link between obesity, cholesterol, and breast cancer

By Jacob Schor, ND, FABNO

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Reference

Wu Q, Ishikawa T, Sirianni R, et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013;5(3):637-645.

Design

The potential impact of the cholesterol metabolite 27-hydroxycholesterol (27-HC) on ER+ breast cancer in women was investigated. Blood markers in cancer patients were compared against healthy controls, seeking possible associations between 27-HC and breast cancer risk and prognosis.

Participants

This study included 66 women with ER positive breast cancer, along with 18 cancer-free controls matched by age and race.

Study Medication and Dosage

There was no drug intervention in this study. 

Outcome Measures

Serum cholesterol and 27-HC were tracked. In addition the 2 cytochrome (CYP) 450 enzymes, CYP27A1 and CYP7B1, that regulate 27-HC were also followed.

Key Findings

“Women with cancer had significantly more 27-HC in their normal breast tissue than controls and even more in their tumors.”1 Levels of 27-HC were 3-fold higher in normal breast tissue of cancer patients and another 2.3 times higher in the actual tumors. No association was seen between tumor 27-HC levels and serum levels of either 27-HC or total cholesterol. Additionally no association was found between serum and healthy breast tissue 27-HC levels. Breast cancer patients with low levels of the enzyme CYP7B1, an enzyme that breaks down 27-HC, did not survive as long as women with high levels.

Practice Implications

This chemical may be the missing link between obesity, cholesterol, and cancer. This story started with the association between obesity and breast cancer, which was never clearly understood. One explanation is that fat tissue increases estrogen levels that in turn may increase breast cancer risk. Another possibility is that type 2 diabetes, a common comorbidity with obesity, elevates insulin and other cancer growth factors. Elevated serum cholesterol had also been linked to breast cancer risk, particularly after menopause, when estrogen levels decrease, but this association had not gotten the attention that it perhaps deserves.

Until recently, estrogen was the only chemical made in the body known to stimulate ER+ breast cancer growth. In 2008 DuSell et al suggested that 27-HC “may influence the pathology of breast cancer.” Umetani and Shaul confirmed this in 2011 when they reported that 27-HC stimulates growth of ER+ breast cancer tumor cells.2

In a separate study also published in November 2013, Nelson et al reported that 27-HC not only stimulates breast cancer growth in petri dishes but also stimulates tumor growth and metastasis in mice.3 This human study by Wu et al certainly gives us reason to believe that 27-HC influences human tumors as well.4

In the breast cancer patients tested in Wu et al’s study, more aggressive tumors had higher levels of CYP27A1, the enzyme that converts cholesterol to 27-HC. Tumors get 27-HC from the blood and also convert cholesterol into 27-HC within their own cells. The enzyme that breaks down 27-HC, CYP7B1, is also important: Patients with low tumor levels of CYP7B1 did not survive as long as patients with high levels.

In a separate animal experiment, Nelson et al implanted breast cancer cells in mice bred to have high cholesterol. Putting these mice on high-fat diets increased production of 27-HC and over a period of 15 days; their tumors grew 30% faster. Treating the mice with statins lowered their cholesterol levels and slowed tumor growth. Chemically blocking CYP27A also slowed tumor growth.5

There is limited information on how 27-HC affects health. Patients with chronic obstructive pulmonary disease (COPD) have high levels of it, and 27-HC may play a role in the fibrotic changes seen in their lung tissues.6 Levels of 27-HC increase with rising cholesterol levels. One theory is that 27-HC “may act as a compensatory mechanism in a condition of larger plasma cholesterol pool”—that is, as a way to manage excess cholesterol.7 High levels of 27-HC are markers of neurodegenerative diseases8 and have been proposed as the link between hypercholestolemia and Alzheimer’s disease.9  

This pair of enzymes, the CYP27A1 enzyme that makes 27-HC and the CYP7B1 enzyme that breaks it down, may in the future provide treatment options. At this point our understanding of how to influence either is limited. It has been reported that dexamethasone, growth hormone, and IGF-1 stimulate CYP27A1 production. Thus these would potentially be ‘bad’ for breast cancer patients. Thyroid hormone (T4) has the opposite effect, inhibiting CYP27A1.10 Dietary phytosterols may also inhibit 27-HC production.11 Statin drugs lower 27-HC levels, and this has been suggested as why they impede breast cancer.

These publications should shift how we view breast cancer. At a minimum we have new biomarkers to follow: 27-HC, CYP27A1, and CYP7B1. These 3 may become targets for treatment. Cholesterol can no longer be seen as unrelated to breast cancer. A number of papers link statin use to improved breast cancer outcomes. In July 2013 Brewer et al reported that statin use by women with inflammatory breast cancer significantly improved progression-free survival, cutting hazard ratios by half.12 In November 2012, Nielsen et al reported that people who take statins had a lower risk of dying from cancer than non-statin users. These researchers had analyzed the causes of death from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, and followed them until December 31, 2009. Of patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins. Those who had taken statins had a 15% lower risk of dying from any cause or from cancer. The reduced cancer-related mortality among statin users was observed for each of 13 cancer types.13

In 2013 Teemu Murtola reported that statin use was associated with up to a 66% reduction in the risk of dying from breast cancer. The death rate among statin users was 7.5%, while among non-statin users it was 21%. Women with localized disease taking statins were 67% less likely to die than nonusers (hazard ratio=0.33).14

Could the possible benefits from taking statins be the result of lowering 27-HC levels? Could other strategies that lower cholesterol levels (eg, diet, exercise) have a similar impact on 27-HC and future cancer risk? We do not know the answers to these questions.

Few medical oncologists concern themselves with cholesterol, considering blood lipids to be the concern of general practitioners or cardiologists. This information should change that. High cholesterol levels may be a clear risk for breast cancer progression in postmenopausal women. Lowering total cholesterol either through lifestyle or drugs may reduce a woman’s risk of getting breast cancer or slow the cancer’s progression. It is time to treat cholesterol in breast cancer patients.

For more research involving integrative oncology, click here.

About the Author

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor.

References

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  2. Umetani M, Shaul PW. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol Metab. 2011;22(4):130-135.
  3. Nelson ER, Wardell SE, Jasper JS, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342(6162):1094-1098.
  4. Wu Q, Ishikawa T, Sirianni R, et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013;5(3):637-645.  
  5. Nelson ER, Wardell SE, Jasper JS, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342(6162):1094-1098.
  6. Kikuchi T, Sugiura H, Koarai A, et al. Increase of 27-hydroxycholesterol in the airways of patients with COPD: possible role of 27-hydroxycholesterol in tissue fibrosis. Chest. 2012;142(2):329-337.  
  7. Bertolotti M, Del puppo M, Corna F, et al. Increased appearance rate of 27-hydroxycholesterol in vivo in hypercholesterolemia: a possible compensatory mechanism. Nutr Metab Cardiovasc Dis. 2012;22(10):823-830. 
  8. Leoni V, Caccia C. Oxysterols as biomarkers in neurodegenerative diseases. Chem Phys Lipids. 2011;164(6):515-224.  
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  10. Araya Z, Tang W, Wikvall K. Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1. Biochem J. 2003;372(Pt 2):529-534.
  11. Brauner R, Johannes C, Ploessl F, Bracher F, Lorenz RL. Phytosterols reduce cholesterol absorption by inhibition of 27-hydroxycholesterol generation, liver X receptor α activation, and expression of the basolateral sterol exporter ATP-binding cassette A1 in Caco-2 enterocytes. J Nutr. 2012;142(6):981-989.
  12. Brewer TM, Masuda H, Liu DD, et al. Statin use in primary inflammatory breast cancer: a cohort study. Br J Cancer. 2013;109(2):318-324.
  13. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792-1802.
  14. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statins and Breast Cancer mortality. Paper presented at: American Association for Cancer Research Annual Meeting; April 7, 2013; Washington, DC.