Associations between lifestyle, health, and clinical characteristics and circulating oxysterols and cholesterol precursors in women diagnosed with breast cancer: a cross-sectional study
Abstract
Despite increasing evidence that cholesterol precursors and oxysterols, oxidized cholesterol metabolites, play a role in numerous pathological processes and diseases including breast cancer, little is known about correlates of these sterols in women with breast cancer. In this study, 2282 women with breast cancer and blood draw post diagnosis were included and cross-sectional associations between circulating levels of 15 sterols/oxysterols and (a) lifestyle, anthropometric, reproductive characteristics, (b) comorbidities and medication use, and (c) breast cancer tumor and treatment characteristics were calculated using generalized linear models. Obesity was strongly associated with circulating levels of 7-dehydrocholesterol (DC) (body mass index ≥ 30 vs. 18.5–24.9 kg/m2: 51.7% difference) and 7-ketocholesterol (KC) (40.0% difference). After adjustment for BMI, comorbidities such as cardiovascular disease were associated with higher levels of 7-DC (26.1% difference) and lower levels of desmosterol (− 16.4% difference). Breast cancer tumor characteristics including hormone receptor status, tumor stage, and endocrine therapy were associated with lanosterol, 24-DHLan, 7b-HC, and THC (e.g., THC; tumor stage IIIa vs. I: 36.9% difference). Weaker associations were observed for lifestyle characteristics and for any of the other oxysterols. The findings of this study suggest that cholesterol precursors are strongly associated with metabolic factors, while oxysterols are associated with breast cancer tumor characteristics, warranting further investigation into the role of cholesterol precursors and oxysterols in women with breast cancer and other populations.
Article type: Research Article
Keywords: Breast cancer, Prognostic markers, Epidemiology
Affiliations: https://ror.org/04cdgtt98grid.7497.d0000 0004 0492 0584Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; https://ror.org/038t36y30grid.7700.00000 0001 2190 4373Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany; https://ror.org/01zgy1s35grid.13648.380000 0001 2180 3484Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; grid.13648.380000 0001 2180 3484Institute for Occupational and Maritime Medicine Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; https://ror.org/02b48z609grid.412315.0University Cancer Center Hamburg, Medical Center Hamburg-Eppendorf, Hamburg, Germany; grid.418193.60000 0001 1541 4204Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway
License: © The Author(s) 2024 CC BY 4.0 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Article links: DOI: 10.1038/s41598-024-55316-x | PubMed: 38424253 | PMC: PMC10904394
Relevance: Relevant: mentioned in keywords or abstract
Full text: PDF (2.2 MB)
References
- V Mutemberezi, O Guillemot-Legris, GG Muccioli. Oxysterols: From cholesterol metabolites to key mediators. Prog. Lipid Res., 2016. [DOI | PubMed]
- AJ Brown, LJ Sharpe, MJ Rogers. Oxysterols: From physiological tuners to pharmacological opportunities. Br. J. Pharmacol., 2021. [DOI | PubMed]
- B Sottero. Lipid oxidation derived aldehydes and oxysterols between health and disease. Eur. J. Lipid Sci. Technol., 2019. [DOI]
- O Guillemot-Legris, V Mutemberezi, GG Muccioli. Oxysterols in metabolic syndrome: From bystander molecules to bioactive lipids. Trends Mol. Med., 2016. [DOI | PubMed]
- A Kloudova, FP Guengerich, P Soucek. The role of oxysterols in human cancer. Trends Endocrinol. Metab. TEM, 2017. [DOI | PubMed]
- WJ Griffiths, Y Wang. Oxysterol research: A brief review. Biochem. Soc. Trans., 2019. [DOI | PubMed]
- DL Lu. Circulating 27-hydroxycholesterol and breast cancer risk: Results from the EPIC-Heidelberg cohort. J. Natl. Cancer Inst., 2019. [DOI | PubMed]
- NS Decker. Endogenous Estrogen receptor modulating oxysterols and breast cancer prognosis: Results from the MARIE patient cohort. Br. J. Cancer, 2023. [DOI | PubMed]
- A Kloudova-Spalenkova. Plasma oxysterol levels in luminal subtype breast cancer patients are associated with clinical data. J. Steroid Biochem. Mol. Biol., 2020. [DOI | PubMed]
- NS Decker. Circulating oxysterols and prognosis among women with a breast cancer diagnosis: results from the MARIE patient cohort. BMC Med., 2023. [DOI | PubMed]
- M Inasu. High CYP27A1 expression is a biomarker of favorable prognosis in premenopausal patients with estrogen receptor positive primary breast cancer. npj Breast Cancer, 2021. [DOI | PubMed]
- S Kimbung. CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients. Breast Cancer Res., 2020. [DOI | PubMed]
- S Kimbung. Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer. Endocrine-Relat. Cancer, 2017. [DOI]
- C Le Cornet, TS Johnson, DL Lu, R Kaaks, RT Fortner. Association between lifestyle, dietary, reproductive, and anthropometric factors and circulating 27-hydroxycholesterol in EPIC-Heidelberg. Cancer Causes Control, 2020. [DOI | PubMed]
- AJ Brown, E Ikonen, VM Olkkonen. Cholesterol precursors: more than mere markers of biosynthesis. Curr. Opin. Lipidol., 2014. [DOI | PubMed]
- A Zmyslowski, A Szterk. Oxysterols as a biomarker in diseases. Clin. Chim Acta, 2019. [DOI | PubMed]
- W Luu, LJ Sharpe, I Capell-Hattam, IC Gelissen, AJ Brown. Oxysterols: Old tale, new twists. Ann. Rev. Pharmacol. Toxicol., 2016. [DOI | PubMed]
- Y Yamauchi, MA Rogers. Sterol metabolism and transport in atherosclerosis and cancer. Front. Endocrinol., 2018. [DOI]
- D Gómez-Coronado, MA Lasunción, J Martínez-Botas, ME Fernández-Suárez. Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators. Sem. Cancer Biol., 2020. [DOI]
- A Möhl. Comorbidity burden in long-term breast cancer survivors compared with a cohort of population-based controls from the MARIE study. Cancer, 2021. [DOI | PubMed]
- K Buck, A Vrieling, D Flesch-Janys, J Chang-Claude. Dietary patterns and the risk of postmenopausal breast cancer in a German case-control study. Cancer Causes Control, 2011. [DOI | PubMed]
- S Abbas. Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer–results of a large case-control study. Carcinogenesis, 2008. [DOI | PubMed]
- A Vrieling. Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study. Breast Cancer Res., 2011. [DOI | PubMed]
- B Rosner. Percentage points for a generalized ESD many-outlier procedure. Technometrics, 1983. [DOI]
- B Hansel. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J. Clin. Endocrinol. Metab., 2004. [DOI | PubMed]
- JF Keaney. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arteriosclerosis Thrombosis Vasc. Biol., 2003. [DOI]
- G Lizard. Glutathione is implied in the control of 7-ketocholesterol-induced apoptosis, which is associated with radical oxygen species production. FASEB J., 1998. [DOI | PubMed]
- S Lemaire-Ewing. Comparison of the cytotoxic, pro-oxidant and pro-inflammatory characteristics of different oxysterols. Cell Biol. Toxicol., 2005. [DOI | PubMed]
- L Baila-Rueda. Cholesterol oversynthesis markers define familial combined hyperlipidemia versus other genetic hypercholesterolemias independently of body weight. J. Nutrit. Biochem., 2018. [DOI | PubMed]
- L Baila-Rueda. Bile acid synthesis precursors in familial combined hyperlipidemia: the oxysterols 24S-hydroxycholesterol and 27-hydroxycholesterol. Biochem. Biophys. Res. Commun., 2014. [DOI | PubMed]
- AR Stiles. Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels. Proc. Natl. Acad. Sci. USA, 2014. [DOI | PubMed]
- R Sato. Sterol metabolism and SREBP activation. Arch. Biochem. Biophys., 2010. [DOI | PubMed]
- J Leignadier, F Dalenc, M Poirot, S Silvente-Poirot. Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death. Biochem. Pharmacol., 2017. [DOI | PubMed]
- JE Rossouw. Relationships of coronary heart disease with 27-hydroxycholesterol, low-density lipoprotein cholesterol, and menopausal hormone therapy. Circulation, 2012. [DOI | PubMed]
- F Dalenc. Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study. J. Steroid Biochem. Mol. Biol., 2017. [DOI | PubMed]
- Q Wu. 27-Hydroxycholesterol promotes cell-autonomous ER-positive breast cancer growth. Cell Rep., 2013. [DOI | PubMed]
- 37.Le Cornet, C. et al. Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1 CYP7B1 LXR-β and ERβ: Results from the EPIC-Heidelberg cohort. Breast Cancer Res.22(1), 23. 10.1186/s13058-020-1253-6 (2020).
- M Tremblay-Franco. Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human. Steroids, 2015. [DOI | PubMed]
- A Ornelas. Beyond COX-1: The effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev., 2017. [DOI | PubMed]
- WY Chen, MD Holmes. Role of aspirin in breast cancer survival. Curr. Oncol. Rep., 2017. [DOI | PubMed]
- MN Passarelli. Association of demographic and health characteristics with circulating oxysterol concentrations. J. Clin. Lipidol., 2022. [DOI | PubMed]
- DL Lu. Reproducibility of serum oxysterols and lanosterol among postmenopausal women: Results from EPIC-Heidelberg. Clin. Biochem., 2018. [DOI | PubMed]
- M Haid. Long-term stability of human plasma metabolites during storage at -80 °C. J. Proteome Res., 2018. [DOI | PubMed]
- A Wagner-Golbs, S Neuber, B Kamlage, N Christiansen, B Bethan, U Rennefahrt, L Lind. Effects of long-term storage at− 80 C on the human plasma metabolome. Metabolites, 2019. [DOI | PubMed]
- S Dzeletovic, O Breuer, E Lund, U Diczfalusy. Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal. Biochem., 1995. [DOI | PubMed]