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Host CYP27A1 Expression Is Essential for Ovarian Cancer Progression

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Host CYP27A1 Expression Is Essential for Ovarian Cancer Progression 26 7 Endocrine-Related S He et al. 27-Hydroxycholesterol 26:7 659–675 Cancer sustains ovarian cancer RESEARCH Host CYP27A1 expression is essential for ovarian cancer progression Sisi He1, Liqian Ma1, Amy E Baek1, Anna Vardanyan1, Varsha Vembar1, Joy J Chen1, Adam T Nelson1, Joanna E Burdette2,5 and Erik R Nelson1,3,4,5,6 1Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 2Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA 3Cancer Center at Illinois, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 4Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 5University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA 6Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois at Urbana Champaign, Urbana, Illinois, USA Correspondence should be addressed to E R Nelson: [email protected] Abstract There is an urgent need for more effective strategies to treat ovarian cancer. Elevated Key Words cholesterol levels are associated with a decreased progression-free survival time (PFS) f cholesterol while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of f ovarian cancer cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) f 27-hydroxycholesterol and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol f tumor microenvironment and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme f myeloid-derived suppressor responsible for the synthesis of 27HC, was associated with decreased PFS, while high cells expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target. Endocrine-Related Cancer (2019) 26, 659–675 Introduction It is expected that there will be approximately 22,530 for 5% of all cancer-related deaths in women (American new cases of ovarian cancer diagnosed in the USA in Cancer Society 2019). Poor survival has been attributed to 2019, accounting for roughly 2.5% of all female cancers the fact that most women present with advanced stages (American Cancer Society 2019). Current therapeutic of the disease, and both de novo and acquired resistance standard of care includes debulking surgery followed by to existing chemotherapy regimens. Therefore, there cycles of chemotherapy, typically paclitaxel combined is a sense of urgency to develop novel diagnostic and with carboplatin. Unfortunately however, ovarian cancer therapeutic approaches for this disease. continues to have an expected 5-year overall survival The majority of ovarian cancers are of epithelial rate of less than 50%, accounting for it being responsible origin, although approximately 2% of cases are germ https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0572 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 07:21:01PM via free access -18-0572 Endocrine-Related S He et al. 27-Hydroxycholesterol 26:7 660 Cancer sustains ovarian cancer cell and 1% are stromal (sex-chord) (American Cancer that cholesterol likely plays an important role in the Society 2019). Epithelial cancers are further subdivided pathophysiology of ovarian cancer and that cholesterol into serous, endometrioid, mucinous and clear cell types, may be one contributing factor to the associations with with serous accounting for the majority (~52%). Of the obesity and worse prognosis. serous tumors, the majority present as high-grade serous Cholesterol is primarily metabolized in the liver carcinomas. Although the ovary itself was considered as by the enzyme CYP7A1 in the traditional bile acid the origin of ovarian cancer (Meyn & Lim 2017), recent synthesis pathway. However, it can also be metabolized evidence suggests that the fallopian tube (oviduct) is likely by CYP27A1 in the acidic bile acid pathway, into the origin for the majority of high-grade serous epithelial 27-hydroxycholesterol (27HC). Intriguingly, several cancers that subsequently spread to the ovaries (Eckert studies have defined 27HC as a ligand for both the et al. 2016, Labidi-Galy et al. 2017). estrogen receptors (ERs) and liver X receptors (LXRs) Although hereditary causes such as mutations in (Umetani et al. 2007, DuSell et al. 2008, Centers for BRCA1 or 2 play important causal roles, they only account Disease Control and Prevention 2010, Nelson et al. for ~20% of cases (Norquist et al. 2016), with the majority 2011, 2013), providing a potential mechanism for of ovarian cancer cases appearing to be spontaneous. High- the actions of cholesterol. As a primary metabolite of grade serous ovarian adenocarcinomas have been found cholesterol, 27HC is the most abundant oxysterol in to predominantly harbor mutations of TP53, with other circulation, and its plasma levels are closely associated common mutations found within NF1, BRCA1, BRCA2, with those of cholesterol (Karuna et al. 2011). Indeed, RB1 and CDK12, although at a much lower prevalence previous studies have found that 27HC promotes breast (Cancer Genome Atlas Research Network et al. 2011). tumor growth by functioning as an ER agonist to induce Gene breakage events often lead to common inactivation cellular proliferation (Nelson et al. 2013, Wu et al. 2013). of RB1, NF1, RAD51 and PTEN (Patch et al. 2015). However, a role for 27HC in ovarian cancer remains Other common genomic alterations include reversions undetermined. Furthermore, unlike in breast cancer, of BRCA1 or 2 mutations, loss of BRCA1 promoter the involvement of the ERs in the pathophysiology methylation, promoter fusion associated with increased of ovarian cancer are not clear. Anti-estrogens appear MDR expression (a multi-drug efflux pump), and altered to only be advantageous in the ovarian endometrioid miRNA expression, etc (Cancer Genome Atlas Research carcinomas and not in the more common high-grade Network et al. 2011, Patch et al. 2015). Furthermore, serous carcinomas (Lindemann et al. 2017). Therefore, enrichment of various T cell populations has been found we initiated a series of studies to define the potential to be associated with a positive prognosis (Yang et al. roles of 27HC in the progression of ovarian cancer . 2018). It is of significance, therefore, that obesity has been associated with an increased risk of ovarian cancer among women who have not taken hormone replacement therapy (Collaborative Group on Epidemiological Studies Materials and methods of Ovarian Cancer 2012). Survival analysis Furthermore, among ovarian cancer patients, obesity is associated with both decreased progression- Kaplan–Meier plots were graphed using Graphpad Prism free and disease-specific survival (PFS and DSS) Nagle( 6 with data and statistical analysis from Kaplan–Meier et al. 2015). While the associations between obesity and plotter [Ovarian Cancer] (http://kmplot.com/analysis/ ovarian cancer are likely complex and multifactorial, it index.php?p=service&cancer=ovar), an online tool for is significant that elevated circulating cholesterol is often genome-wide validation of survival-associated biomarkers observed in obese patients (Must et al. 1999, Gostynski (Gyorffy et al. 2010, 2012). et al. 2004, Centers for Disease Control and Prevention Forest plots were generated using R 3.5.0 (https:// 2010), and a strong association exists between elevated www.r-project.org/) using the curated OvarianData package plasma LDL cholesterol and decreased PFS and DSS (Li (Haibe-Kains et al. 2012, Ganzfried et al. 2013). Databases et al. 2010). Conversely, patients taking cholesterol- and patients with relevant survival information (OS or lowering drugs (inhibitors of HMGCoA-reductase; statins) PFS) were selected and gene expressions were rescaled to have been found to have significantly increased PFS and z-score for analysis. survival and metafor packages were DSS (Elmore et al. 2008, Lavie et al. 2013, Habis et al. 2014, used to calculate hazard ratios and generate forest plots. Akinwunmi et al. 2019). Collectively, these data indicate R script available upon request. https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0572 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 07:21:01PM via free access Endocrine-Related S He et al. 27-Hydroxycholesterol 26:7 661 Cancer sustains ovarian cancer Data containing progression-free survival and Animal models tumoral CYP27A1 or CYP7B1 expression were extracted All animal experiments and procedures were approved from the Kaplan–Meier Plotter with auto select best cutoff by the Institutional Animal Care and Use Committee and follow up threshold of 5 years. A total of 1435 ovarian (IACUC) at University
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