Abstract
Purpose
27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM), drives the growth of estrogen receptor-positive (ER+) breast cancer. 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, is known to inhibit expression of CYP27B1, which is very similar in structure and function to CYP27A1, the synthesizing enzyme of 27HC. Therefore, we hypothesized that 1,25(OH)2D may also inhibit expression of CYP27A1, thereby reducing 27HC concentrations in the blood and tissues that express CYP27A1, including breast cancer tissue.
Methods
27HC, 25-hydroxyvitamin D (25OHD), and 1,25(OH)2D were measured in sera from 29 breast cancer patients before and after supplementation with low-dose (400 IU/day) or high-dose (10,000 IU/day) vitamin D in the interval between biopsy and surgery.
Results
A significant increase (p = 4.3E−5) in 25OHD and a decrease (p = 1.7E−1) in 27HC was observed in high-dose versus low-dose vitamin D subjects. Excluding two statistical outliers, 25OHD and 27HC levels were inversely correlated (p = 7.0E−3).
Conclusions
Vitamin D supplementation can decrease circulating 27HC of breast cancer patients, likely by CYP27A1 inhibition. This suggests a new and additional modality by which vitamin D can inhibit ER+ breast cancer growth, though a larger study is needed for verification.
Abbreviations
- 1,25(OH)2D:
-
1,25-Dihydroxyvitamin D
- 25OHD:
-
25-Hydroxyvitamin D
- 27HC:
-
27-Hydroxycholesterol
- ER+:
-
Estrogen receptor-positive
- LC–MS/MS:
-
Liquid chromatography tandem mass spectrometry
- SERM:
-
Selective estrogen receptor modulator
- SRM:
-
Selected reaction monitoring
References
Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, Mangelsdorf DJ (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med 13:1185–1192
DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP (2008) 27-Hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol 22:65–77
Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B, Girard L, Mineo C, Brekken RA, Umetani M, Euhus DM, Xie Y, Shaul PW (2013) 27-Hydroxycholesterol promotes cell-autonomous ER-positive breast cancer growth. Cell Rep 5:637–645
Nelson ER, Wardell SE, McDonnell DP (2015) Abstract A82: the cholesterol metabolite, 27-hydroxycholesterol, promotes breast cancer metastasis. Cancer Immunol Res 3:A82
Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342:1094–1098
Kimbung S, Chang C, Bendahl P-O, Dubois L, Thompson WJ, McDonnell DP, Borgquist S (2017) Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer. Endocr Relat Cancer 24:339–349
Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW (2013) Molecular mechanisms of vitamin D action. Calcif Tissue Int 92:77–98
Krishnan AV, Feldman D (2011) Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 51:311–336
Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ (2014) The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 14:342–357
Luo W, Johnson CS, Trump DL (2016) Vitamin D signaling modulators in cancer therapy. Vitam Horm 100:433–472
Takeyama K-i, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S (1997) 25-Hydroxyvitamin D3 1α-hydroxylase and vitamin D synthesis. Science 277:1827–1830
Murayama A, Takeyama K-i, Kitanaka S, Kodera Y, Hosoya T, Kato S (1998) The promoter of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)2D3. Biochem Biophys Res Commun 249:11–16
Jones G, Prosser DE, Kaufmann M (2014) Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 55:13–31
Axen E, Postland H, Sioberg H, Wikvall K (1994) Liver mitochondrial cytochrome P450 CYP27 and recombinant-expressed human CYP27 catalyze 1 alpha-hydroxylation of 25-hydroxyvitamin D3. Proc Natl Acad Sci USA 91:10014–10018
Sawada N, Sakaki T, Ohta M, Inouye K (2000) Metabolism of vitamin D3 by CYP27A1. Biochem Biophys Res Commun 273:977–984
Yin K, You Y, Swier V, Tang L, Radwan MM, Pandya AN, Agrawal DK (2015) Vitamin D protects against atherosclerosis via regulation of cholesterol efflux and macrophage polarization in hypercholesterolemic swine. Arterioscler Thromb Vasc Biol 35:2432–2442
Barchetta I, Carotti S, Labbadia G, Gentilucci UV, Muda AO, Angelico F, Silecchia G, Leonetti F, Fraioli A, Picardi A, Morini S, Cavallo MG (2012) Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus. Hepatology 56:2180–2187
McDonald JG, Smith DD, Stiles AR, Russell DW (2012) A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma. J Lipid Res 53:1399–1409
Vanlint S (2013) Vitamin D and Obesity. Nutrients 5:949–956
Swami S, Krishnan AV, Williams J, Aggarwal A, Albertelli MA, Horst RL, Feldman BJ, Feldman D (2016) Vitamin D mitigates the adverse effects of obesity on breast cancer in mice. Endocr Relat Cancer 23:251–264
Swami S, Krishnan AV, Wang JY, Jensen K, Horst R, Albertelli MA, Feldman D (2012) Dietary vitamin D(3) and 1,25-dihydroxyvitamin D(3) (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology 153:2576–2587
Townsend K, Banwell CM, Guy M, Colston KW, Mansi JL, Stewart PM, Campbell MJ, Hewison M (2005) Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res 11:3579–3586
Kemmis CM, Salvador SM, Smith KM, Welsh J (2006) Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3. J Nutr 136:887–892
Krishnan AV, Swami S, Feldman D (2013) Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention. J Steroid Biochem Mol Biol 136:289–295
Wagner D, Trudel D, Van der Kwast T, Nonn L, Giangreco AA, Li D, Dias A, Cardoza M, Laszlo S, Hersey K, Klotz L, Finelli A, Fleshner N, Vieth R (2013) Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. J Clin Endocrinol Metab 98:1498–1507
Aggarwal A, Feldman D, Feldman BJ (2017) Identification of tumor-autonomous and indirect effects of vitamin D action that inhibit breast cancer growth and tumor progression. J Steroid Biochem Mol Biol. https://doi.org/10.1016/j.jsbmb.2017.07.003
Williams JD, Aggarwal A, Swami S, Krishnan AV, Ji L, Albertelli MA, Feldman BJ (2016) Tumor autonomous effects of vitamin D deficiency promote breast cancer metastasis. Endocrinology 157:1341–1347
Nguyen VTM, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P, Castellano L, Győrffy B, Woodley L, Meira A, Patten DK, Vircillo V, Periyasamy M, Ali S, Frige G, Minucci S, Coombes RC, Magnani L (2015) Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nat Commun 6:10044
Acknowledgements
The authors would like to acknowledge funding for this project from the Vincent Coates Foundation Mass Spectrometry Laboratory in the form of a SUMS Seed Grant. We are grateful to Dr. Melinda Telli, Dr. Kristin Jensen, and members of the Feldman Lab that carried out this trial for their generous access to serum specimens of many of the subjects.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Going, C.C., Alexandrova, L., Lau, K. et al. Vitamin D supplementation decreases serum 27-hydroxycholesterol in a pilot breast cancer trial. Breast Cancer Res Treat 167, 797–802 (2018). https://doi.org/10.1007/s10549-017-4562-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-017-4562-4