Three New Biomarkers of Interest for Breast Cancer

by Jacob Schor, ND, FABNO

Three lab tests, though not yet available, may prove useful for menopausal breast cancer patients. Hopefully this article will inspire some laboratory to offer them. The tests are 27-hydroxycholesterol (27-HC), CYP27A1, and CYP7B1.

These tests may help determine prognosis and to advocate for certain treatments.

The most interesting of these three tests is 27-HC. This chemical is a cholesterol metabolite and recently determined to act as a selective estrogen receptor modulator (SERM), stimulating ER+ breast cancer cells to grow. Until recently, estrogen was the only chemical made in the body known to stimulate growth in this way. This changed in 2008 when DuSell reported 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. ¹

A pair of studies published in November 2013 confirmed these effects in animals and humans. 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.² A human study, part of a larger paper by Wu et al., gives us reason to believe that 27-HC influences human tumors as well. ³

(27-OHC), a cholesterol metabolite that is different in structure but similar in action to estradiol, could plausibly confer the same benefits and risks as estradiol. On the one hand, it might protect postmenopausal women from osteoporosis and the drying of skin and mucous membranes. On the other, it might increase the risk of breast cancer. Does one role predominate?⁴

Wu et al. compared levels of serum cholesterol, 27-hydroxycholesterol (27-HC), CYP27A1 and CYP7B1 in 66 women with ER positive breast cancer with levels in 18 cancer-free women matched by age and race.

Remember, 27-hydroxycholesterol (27-HC) is a cholesterol metabolite. The two CYP450 enzymes, CYP27A1 and CYP7B1, regulate 27-HC; CYP27A1 is the enzyme that makes 27-HC while CYP7B1 breaks it down.

Wu found that “Women with cancer had significantly more 27-HC in their normal breast tissue than controls and even more in their tumors.” 27-HC levels were 3-fold higher in normal breast tissue of cancer patients and another 2.3 times higher in the actual tumors. Breast cancer patients with low levels of the enzyme CYP7B1, the enzyme that breaks down 27-HC, did not survive as long as women with high levels.^5,6

While it is tempting to think that testing women for these biomarkers will be useful, this might not be as straightforward as we would wish. In Wu’s data, no association was seen between tumor 27-HC levels and serum levels of either 27-HC or total cholesterol, so simply measuring blood serum levels of either might not help; no association was found between serum levels and healthy breast tissue 27-HC levels. So simple blood tests may not be as helpful as we would wish. Levels of these enzymes may prove more useful.

This chemical 27-HC may prove to be the missing link between metabolic syndrome, obesity, cholesterol, and estrogen-sensitive cancers.⁷ Quite a few cancers are strongly associated with obesity, including “endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal” cancer.^8,9 Elevated cholesterol levels promote formation of larger tumors and enhance metastasis. The increased conversion of cholesterol to 27-HC may be the explanation that links these conditions to cancer.¹⁰ Of these cancers, a few seem to be stimulated by estrogen, and so aromatase inhibitors may be useful to lower estrogen. While this strategy is well established for treating breast cancer, there are suggestions that aromatase inhibition may prove useful for endometrial and ovarian cancers.^11,12 Reducing 27-HC could play a role in more than breast cancer.

In the breast cancer patients tested in Wu’s study, the more aggressive tumors had higher levels of CYP27A1, the enzyme that converts cholesterol to 27-HC. Tumors get 27-HC from the blood but 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.

Thus both of these enzymes could become treatment targets; lower the CYP27A1 and/or increase CYP7B1 if you can.

In a separate animal experiment, Nelson implanted mice bred to have high cholesterol with breast cancer cells. Putting these mice on high-fat diets increased production of 27-HC and over a period of 15 days, their tumors grew 30% more. (This provides a rationale for menopausal women with ER + BC to avoid high-fat diets.) Treating these mice with statins, both lowered their cholesterol levels and slowed tumor growth. Chemically blocking CYP27A also slowed tumor growth.

There is limited information on how 27-HC affects health. Patients with chronic obstructive pulmonary disease (COPD) have high levels, and it is thought that the 27-HC may play a role in the fibrotic changes seen in their lung tissues.¹³ 27-HC levels increase with rising cholesterol levels and 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.¹⁴ High levels of 27-HC are markers of neurodegenerative diseases and have been proposed as the link between hypercholesterolemia and Alzheimer’s disease.^15,16

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. Well we, kind of already knew that. Thyroid hormone (T4) has the opposite effect, inhibiting CYP27A1.¹⁷ This may be an argument for being more forward in treating subclinical hypothyroidism in breast cancer patients.

Dietary phytosterols may also inhibit 27-HC production.¹⁸ Perhaps some of the natural cholesterol lowering agents will do the same thing as statins? It is clear, though, that statins lower 27-HC levels, and this may be why these drugs appear to sometimes impede breast cancer.

These recent publications should shift how we view breast cancer. At a minimum, we have new biomarkers to follow, 27-HC, CYP27A1, and CYP7B1, biomarkers that could 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.¹⁹ 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 Danes 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.²⁰

In 2013, Teemu Murtola associated statin use with a possible 66% reduction in risk of dying from breast cancer. 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).²¹

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

Information from two recent papers published in August and September 2015 should be added to the considerations that a woman with a history of breast cancer and her oncologist need to ponder in making her choice of adjunctive treatments, whether she takes tamoxifen or an aromatase inhibitor.

Norman Javitt reported in August 2015 in the journal Steroids that tamoxifen blocks several steps in the cholesterol metabolic pathway so that, “In genetically disposed women, tamoxifen may increase the amount of 27-hydroxycholesterol in breast tissue.”²² This fact might argue against using tamoxifen in obese women with high cholesterol. Knowing their levels of 27-HC, CYP27A1 and CYP7B1 might help inform a decision.

Last September, Natalia Mast et al. identified half a dozen drugs already on the market that inhibit CYP27A1 and that might thus be useful in lowering 27-HC. Two of them, anastrozole (Arimidex) and fadrozole (Afema) are aromatase inhibitors and are already used to treat breast cancer.²³ When tested in mice, anastrozole lowered plasma 27-HC 2.6-fold in a week. Thus anastrozole, a drug already on offer, might offer dual benefit for certain women over letrozole (Femara), lowering not just estrogen but also 27-HC.²⁴

Medical oncologists rarely concern themselves with cholesterol, considering blood lipids to be the province of general practitioners and cardiologists. It is time to change this. High cholesterol levels may be a clear risk for breast cancer progression in ER+ postmenopausal women. Lowering total cholesterol, either through lifestyle or drugs, could reduce a woman’s risk of getting breast cancer or slow the cancer’s progression. It is tempting to write that all medical practitioners must concern themselves with the whole patient, but doing so would be kind of preaching to the choir when writing for the Townsend Letter; yet it is hard to think of a better way to express this. It is certainly high time that we pay attention to and be concerned about cholesterol in breast cancer patients.

Notes

1. Umetani M, Shaul PW. 27-Hydroxycholesterol: the first identified endogenous SERM.

Trends Endocrinol Metab. 2011 Apr;22(4):130–135. doi:10.1016/j.tem.2011.01.003. Epub 2011 Feb 23.

2. Nelson ER, Wardell SE, Jasper JS, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013 Nov 29;342(6162):1094–1098. doi:10.1126/science.1241908.

3. Wu Q, Ishikawa T, Sirianni R, et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013 Nov 14;5(3):637–645.

4. Warner M, Gustafsson JA. On estrogen, cholesterol metabolism, and breast cancer. N Engl J Med. 2014 Feb 6;370(6):572–573. doi:10.1056/NEJMcibr1315176.

5. Kaiser J. Cholesterol forges link between obesity and breast cancer. Science. 2013 Nov 29;342(6162):1028. doi:10.1126/science.342.6162.1028.

6. Wu Q, Ishikawa T, Sirianni R, et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013 Nov 14;5(3):637–645. doi:10.1016/j.celrep.2013.10.006. Epub 2013 Nov 7.

7. Lee WR, Ishikawa T, Umetani M. The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol. Clin Lipidol. 2014;9(6):617–624.

8. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546. doi:10.1155/2013/291546. Epub 2013 Aug 29.

9. McDonnell DP, Park S, Goulet MT, et al. Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res. 2014 Sep 15;74(18):4976–4982. doi:10.1158/0008-5472.CAN-14-1756. Epub 2014 Jul 24.

10. Ben-Shmuel S, Rostoker R, Scheinman EJ, LeRoith D. Metabolic syndrome, type 2 diabetes, and cancer: epidemiology and potential mechanisms. Handb Exp Pharmacol. Epub 2015 Apr 23.

11. Thangavelu A, Hewitt MJ, Quinton ND, Duffy SR. Neoadjuvant treatment of endometrial cancer using anastrozole: a randomised pilot study. Gynecol Oncol. 2013 Dec;131(3):613–618. doi:10.1016/j.ygyno.2013.09.023. Epub 2013 Sep 27.

12. Hirakawa H, Yokoyama Y, Yoshida H, Mizunuma H. Inhibitory effects of aromatase inhibitor on estrogen receptor-alpha positive ovarian cancer in mice. J Ovarian Res. 2014 Jan 10;7(1):4. doi:10.1186/1757-2215-7-4.

13. 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 Aug;142(2):329–337.

14. 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 Oct;22(10):823–830. doi:10.1016/j.numecd.2011.02.009. Epub 2011 May 4.

15. Leoni V, Caccia C. Oxysterols as biomarkers in neurodegenerative diseases. Chem Phys Lipids. 2011 Sep;164(6):515–524. doi:10.1016/j.chemphyslip.2011.04.002. Epub 2011 Apr 16.

16. Björkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U. Oxysterols and Alzheimer’s disease. Acta Neurol Scand Suppl. 2006;185:43–49.

17. Araya Z, Tang W, Wikvall K. Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1. Biochem J. 2003;372:529–534. doi:10.1042/BJ20021651.

18. 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 Jun;142(6):981–989. doi:10.3945/jn.111.157198. Epub 2012 Apr 25.

19. Brewer TM, Masuda H, Liu DD, et al. Statin use in primary inflammatory breast cancer: a cohort study. Br J Cancer. 2013 Jul 23;109(2):318-24. doi:10.1038/bjc.2013.342. Epub 2013 Jul 2.

20. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012 Nov 8;367(19):1792–1802.

21. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statins and breast cancer mortality. American Association for Cancer Research Annual Meeting; April 7, 2013.

22. Javitt NB. Breast cancer and (25R)-26-hydroxycholesterol. Steroids. Epub 2015 Aug 20. pii:S0039-128X(15)00226-3. doi:10.1016/j.steroids.2015.08.012.

23. Fadrozole is licensed for use in Japan but apparently not in the US.

24. Mast N, Lin JB, Pikuleva IA. Marketed drugs can inhibit cytochrome P450 27A1, a potential new target for breast cancer adjuvant therapy. Mol Pharmacol. 2015 Sep;88(3):428–436. doi:10.1124/mol.115.099598. Epub 2015 Jun 16.