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Circulating 27-Hydroxycholesterol and Breast Cancer Tissue Expression of CYP27A1, CYP7B1, LXR-Β, and Erβ

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Circulating 27-Hydroxycholesterol and Breast Cancer Tissue Expression of CYP27A1, CYP7B1, LXR-Β, and Erβ Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ Le Cornet, C., Walter, B., Sookthai, D., Johnson, T. S., Kühn, T., Herpel, E., Kaaks, R., & Fortner, R. T. (2020). Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort. Breast Cancer Research, 22(1), 23. https://doi.org/10.1186/s13058- 020-1253-6 Published in: Breast Cancer Research Document Version: Publisher's PDF, also known as Version of record Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights © 2020 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:27. Sep. 2021 Le Cornet et al. Breast Cancer Research (2020) 22:23 https://doi.org/10.1186/s13058-020-1253-6 RESEARCH ARTICLE Open Access Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort Charlotte Le Cornet1, Britta Walter2, Disorn Sookthai1, Theron S. Johnson1, Tilman Kühn1, Ester Herpel2,3, Rudolf Kaaks1 and Renée T. Fortner1* Abstract Background: Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7- alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERβ) may impact the association between 27HC and breast cancer risk. Methods: We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-β,andERβ and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested case- control study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography–mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1- negative cases, whereas a higher proportion of ERβ-positive cases were Bcl-2 low, relative to ERβ-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ, with the exception of statistically significant heterogeneity by LXR-β status in the subgroup of women perimenopausal at blood collection (p =0.02). Conclusion: This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-β,orERβ. Keywords: 27-hydroxycholeterol, Tissue microarray, Immunohistochemistry, Cholesterol metabolism, Breast cancer * Correspondence: [email protected] 1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Le Cornet et al. Breast Cancer Research (2020) 22:23 Page 2 of 10 Introduction associations between (i) protein expression of these 27-Hydroxycholesterol (27HC) is an abundant oxysterol markers in the breast tumor tissue and breast cancer in blood and plays an intermediate role in cholesterol case characteristics, (ii) protein expression of these catabolism to bile acids. Two key enzymes produced markers in the breast tumor tissue and epidemiological from cytochrome P450 genes are involved in 27HC factors and circulating sex steroids and lipids, and (iii) regulation: cholesterol 27-hydroxylase (CYP27A1) and prediagnostic 27HC concentrations in blood and breast oxysterol 7-alpha-hydroxylase (CYP7B1). CYP27A1 is re- cancer risk by these markers. This was an exploratory sponsible for conversion of cholesterol into 27HC study in which we hypothesized potential differential whereas CYP7B1 catabolizes 27HC toward bile acid syn- protein expression by case characteristics (e.g., CYP27A1 thesis [1]. Experimental studies identified 27HC as an associated with favorable prognostic characteristics such endogenous selective estrogen receptor modulator as tumor grade), and heterogeneity in associations be- (SERM) [2]. 27HC binds to both the estrogen receptor tween 27HC and breast cancer risk by tumor protein ex- alpha (ERα) and estrogen receptor beta (ERβ)[2, 3], pression (e.g., stronger association between 27HC and though with greater affinity for ERβ [3]. Although the breast cancer among cases with CYP27A1-positive tu- precise roles of ERβ in breast cancer remain to be delin- mors). This study was conducted within the Heidelberg, eated [4], ERβ was demonstrated to be expressed in a Germany cohort of the European Investigation into Can- majority of breast cancers, including those lacking ERα cer and Nutrition (EPIC). expression. Independent from estrogen receptor (ER)- mediated actions, 27HC is a liver X receptor (LXR) lig- Materials and methods and [5] and has been implicated in breast cancer metas- Study population: the EPIC-Heidelberg cohort tasis via the LXR in experimental animal models [6]. The EPIC-Heidelberg cohort includes 25,540 study par- The role of 27HC in the etiology and progression of ticipants (13,611 women) recruited between 1994 and breast cancer has been investigated in experimental ani- 1998 with between ages 35 and 65 years. Blood samples, mal models [6, 7], with limited data in epidemiologic anthropometric, reproductive, and epidemiologic factors studies and patient populations to date [8–10]. In ex- including diet and lifestyle behavior were collected at perimental cell-line models, 27HC induced cell prolifera- baseline and described previously [12, 13]. Blood sam- tion through ER activation, though administration of ples are stored under liquid nitrogen (− 196 °C) at the 27HC reduced estradiol-induced proliferation [2]. German Cancer Research Center (DKFZ, Heidelberg, Higher 27HC was associated with disease progression in Germany). experimental animal models [6, 7]. One prospective trial in breast cancer patients reported a significant increase Case identification of 27HC in response to aromatase inhibitor but not to All incident cases of invasive breast cancer were identi- tamoxifen treatment [9]. Our group previously published fied and verified by study physicians during prospective on prediagnosis circulating 27HC and breast cancer risk, follow-up (through January 2013), by active follow-up reporting an inverse association between circulating with study participants or derived from hospital records, 27HC and breast cancer risk in postmenopausal women or cancer and mortality registries. Each participant case and no significant heterogeneity by tumor ERα status was free of any previous invasive cancer (with the excep- (clinically measured) [8]. Higher tumor CYP27A1 mRNA tion of non-melanoma skin cancer) or in situ breast can- expression has been associated with better prognosis in cer history prior to invasive breast cancer diagnosis, and women 50 or younger and with ERα-positive breast can- had a blood sample available collected at baseline. Over- cer [10], though other studies have not observed an as- all, 530 cases met these criteria, including 287 (54.1%) sociation in a broader population [6, 7]. CYP7B1 for which tumor blocks were available and who were in- expression has been shown to be lower in ERα-positive cluded on a tissue microarray (TMA). breast tumors, relative to normal
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