{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:45:21Z","timestamp":1782924321451,"version":"3.54.5"},"posted":{"date-parts":[[2025,12,15]]},"group-title":"Genomics","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["R21 CA270580"],"award-info":[{"award-number":["R21 CA270580"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Estrogen receptor alpha (ER) is an established oncogenic transcription factor in breast and endometrial cancer; however, more is known about the mechanisms controlling ER behavior in breast cancer, and therapies targeting ER have been much more successful in breast cancer. To address this disparity, we characterize the genomic features that control ER in endometrial cancer and determine to what extent these factors differ from those in breast cancer. We focus on the locations of estrogen response elements (EREs), ER\u2019s preferred DNA binding motif, throughout the human genome. To identify factors that predict ER genomic binding and effects on target gene expression, we apply machine learning to genomic data for each ERE in Ishikawa cells (ER-positive endometrial cancer) and T-47D cells (ER-positive breast cancer). Many of these factors, such as chromatin accessibility and histone modifications, are predictive of ER activity in both cell lines. However, the transcription factors that predict ER activity are cell type-specific, including FOXA1 and GATA3 in T-47D cells, and ETV4 and SOX17 in Ishikawa cells. In addition, the features that predict ER binding and effects on gene expression differ, with transcription at EREs in the absence of estrogen being predictive of ER regulatory activity. A CRISPR knockout screen in Ishikawa cells, and follow-up experiments, confirm the discovery that SOX17 controls ER activity in endometrial cancer cells. These results identify important genomic features of ER binding and regulatory activity and how these features differ between endometrial cancer and breast cancer cells.<\/jats:p>","DOI":"10.64898\/2025.12.11.693723","type":"posted-content","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T16:45:15Z","timestamp":1765817115000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of genomic features that uniquely impact estrogen receptor alpha binding and its effects on gene expression in endometrial cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1297-8006","authenticated-orcid":false,"given":"Alexandra","family":"Richey","sequence":"first","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4509-3861","authenticated-orcid":false,"given":"Noel","family":"Kitchen","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1036-6909","authenticated-orcid":false,"given":"Craig M.","family":"Rush","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-1513","authenticated-orcid":false,"given":"Jeffery M.","family":"Vahrenkamp","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3003-1177","authenticated-orcid":false,"given":"Hosiana","family":"Abewe","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-7040","authenticated-orcid":false,"given":"Kyle S.","family":"Osbourne","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2273-8922","authenticated-orcid":false,"given":"Alex J.","family":"Bott","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9774-5200","authenticated-orcid":false,"given":"Brian K.","family":"Dalley","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2710-9765","authenticated-orcid":false,"given":"Jared","family":"Rutter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"},{"name":"Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7568-6789","authenticated-orcid":false,"given":"Jason","family":"Gertz","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070108501007000_2025.12.11.693723v2.1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.279699.124"},{"key":"2026070108501007000_2025.12.11.693723v2.2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.203380"},{"key":"2026070108501007000_2025.12.11.693723v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"2026070108501007000_2025.12.11.693723v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2688"},{"key":"2026070108501007000_2025.12.11.693723v2.5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cels.2017.08.011","article-title":"Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor \u03b1-Bound Enhancers","volume":"5","year":"2017","journal-title":"Cell Systems"},{"key":"2026070108501007000_2025.12.11.693723v2.6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa454"},{"key":"2026070108501007000_2025.12.11.693723v2.7","doi-asserted-by":"crossref","unstructured":"Ciocia A , Mestre-Farr\u00e0s N , Vicent-Nacht I , Guitart T , Gebauer F. 2024. CSDE1: a versatile regulator of gene expression in cancer. NAR Cancer 6.","DOI":"10.1093\/narcan\/zcae014"},{"key":"2026070108501007000_2025.12.11.693723v2.8","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.5.1884-1896.2004"},{"key":"2026070108501007000_2025.12.11.693723v2.9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1813"},{"key":"2026070108501007000_2025.12.11.693723v2.10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-011420-095916"},{"key":"2026070108501007000_2025.12.11.693723v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/nature08497"},{"key":"2026070108501007000_2025.12.11.693723v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.08.037"},{"key":"2026070108501007000_2025.12.11.693723v2.13","doi-asserted-by":"crossref","first-page":"100542","DOI":"10.1016\/j.xgen.2024.100542","article-title":"Cis-regulatory control of transcriptional timing and noise in response to estrogen","volume":"4","year":"2024","journal-title":"Cell Genom"},{"key":"2026070108501007000_2025.12.11.693723v2.14","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201900497"},{"key":"2026070108501007000_2025.12.11.693723v2.15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13059-025-03596-5","article-title":"Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations","volume":"26","year":"2025","journal-title":"Genome Biol"},{"key":"2026070108501007000_2025.12.11.693723v2.16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl372"},{"key":"2026070108501007000_2025.12.11.693723v2.17","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ygyno.2015.01.336","article-title":"The role of Sox17 in endometrial gland formation and carcinogenesis","volume":"137","year":"2015","journal-title":"Gynecol Oncol"},{"key":"2026070108501007000_2025.12.11.693723v2.18","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24696"},{"key":"2026070108501007000_2025.12.11.693723v2.19","doi-asserted-by":"publisher","DOI":"10.1210\/en.140.12.5566"},{"key":"2026070108501007000_2025.12.11.693723v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"2026070108501007000_2025.12.11.693723v2.21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/15.7.563"},{"key":"2026070108501007000_2025.12.11.693723v2.22","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2015.2962"},{"key":"2026070108501007000_2025.12.11.693723v2.23","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00055-16"},{"key":"2026070108501007000_2025.12.11.693723v2.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(00)01551-6"},{"key":"2026070108501007000_2025.12.11.693723v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.730"},{"key":"2026070108501007000_2025.12.11.693723v2.26","doi-asserted-by":"publisher","DOI":"10.7150\/thno.34874"},{"key":"2026070108501007000_2025.12.11.693723v2.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.1141319"},{"key":"2026070108501007000_2025.12.11.693723v2.28","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706399"},{"key":"2026070108501007000_2025.12.11.693723v2.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2006.10.009"},{"key":"2026070108501007000_2025.12.11.693723v2.30","doi-asserted-by":"publisher","DOI":"10.1101\/gr.229102. Article published online before print in May 2002"},{"key":"2026070108501007000_2025.12.11.693723v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0201-4"},{"key":"2026070108501007000_2025.12.11.693723v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-51751-3"},{"key":"2026070108501007000_2025.12.11.693723v2.33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.2.647"},{"key":"2026070108501007000_2025.12.11.693723v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2011.59"},{"key":"2026070108501007000_2025.12.11.693723v2.35","first-page":"48","article-title":"Package \u2018caret\u2019","volume":"223","year":"2020","journal-title":"The R Journal"},{"key":"2026070108501007000_2025.12.11.693723v2.36","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v036.i11"},{"key":"2026070108501007000_2025.12.11.693723v2.37","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"2026070108501007000_2025.12.11.693723v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.06.063"},{"key":"2026070108501007000_2025.12.11.693723v2.39","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD011093.pub2"},{"key":"2026070108501007000_2025.12.11.693723v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature12113"},{"key":"2026070108501007000_2025.12.11.693723v2.41","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.13.659603"},{"key":"2026070108501007000_2025.12.11.693723v2.42","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2026070108501007000_2025.12.11.693723v2.43","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"2026070108501007000_2025.12.11.693723v2.44","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026070108501007000_2025.12.11.693723v2.45","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/ijc.32922","article-title":"ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer","volume":"147","year":"2020","journal-title":"Int J Cancer"},{"key":"2026070108501007000_2025.12.11.693723v2.46","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026070108501007000_2025.12.11.693723v2.47","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/bjc.2012.241","article-title":"Pair-Box (PAX8) protein-positive expression is associated with poor disease outcome in women with endometrial cancer","volume":"107","year":"2012","journal-title":"Br J Cancer"},{"key":"2026070108501007000_2025.12.11.693723v2.48","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00740-2"},{"key":"2026070108501007000_2025.12.11.693723v2.49","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02322-1"},{"key":"2026070108501007000_2025.12.11.693723v2.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2016.03.013"},{"key":"2026070108501007000_2025.12.11.693723v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2014.06.012"},{"key":"2026070108501007000_2025.12.11.693723v2.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.04.019"},{"key":"2026070108501007000_2025.12.11.693723v2.53","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"2026070108501007000_2025.12.11.693723v2.54","unstructured":"R Core Team. 2016. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http:\/\/www.R-project.org\/."},{"key":"2026070108501007000_2025.12.11.693723v2.55","first-page":"4763","article-title":"Classification of gene expression data with optimized feature selection","volume":"8","year":"2019","journal-title":"Int J Recent Technol Eng"},{"key":"2026070108501007000_2025.12.11.693723v2.56","first-page":"44","article-title":"Alteration of GLIS3 gene expression pattern in patients with breast cancer","volume":"5","year":"2016","journal-title":"Adv Biomed Res"},{"key":"2026070108501007000_2025.12.11.693723v2.57","doi-asserted-by":"publisher","DOI":"10.1101\/gr.097022.109"},{"key":"2026070108501007000_2025.12.11.693723v2.58","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"2026070108501007000_2025.12.11.693723v2.59","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-019-0358-9"},{"key":"2026070108501007000_2025.12.11.693723v2.60","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-1382"},{"key":"2026070108501007000_2025.12.11.693723v2.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.04.020"},{"key":"2026070108501007000_2025.12.11.693723v2.62","doi-asserted-by":"publisher","DOI":"10.1038\/nature10730"},{"key":"2026070108501007000_2025.12.11.693723v2.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-24211-8"},{"key":"2026070108501007000_2025.12.11.693723v2.64","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12943-024-02071-2","article-title":"Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers","volume":"23","year":"2024","journal-title":"Mol Cancer"},{"key":"2026070108501007000_2025.12.11.693723v2.65","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s10555-025-10275-1","article-title":"CRISPR screening approaches in breast cancer research","volume":"44","year":"2025","journal-title":"Cancer Metastasis Rev"},{"key":"2026070108501007000_2025.12.11.693723v2.66","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047"},{"key":"2026070108501007000_2025.12.11.693723v2.67","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13112"},{"key":"2026070108501007000_2025.12.11.693723v2.68","doi-asserted-by":"crossref","first-page":"100038","DOI":"10.1016\/j.modpat.2022.100038","article-title":"Identifying SOX17 as a Sensitive and Specific Marker for Ovarian and Endometrial Carcinomas","volume":"36","year":"2023","journal-title":"Mod Pathol"},{"key":"2026070108501007000_2025.12.11.693723v2.69","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"2026070108501007000_2025.12.11.693723v2.70","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-6-41"},{"key":"2026070108501007000_2025.12.11.693723v2.71","doi-asserted-by":"publisher","DOI":"10.1261\/rna.2192803"},{"key":"2026070108501007000_2025.12.11.693723v2.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1969-6"},{"key":"2026070108501007000_2025.12.11.693723v2.73","doi-asserted-by":"publisher","DOI":"10.1101\/gr.139469.112"},{"key":"2026070108501007000_2025.12.11.693723v2.74","doi-asserted-by":"crossref","first-page":"113268","DOI":"10.1016\/j.isci.2025.113268","article-title":"A 3D genome compendium of breast cancer progression","volume":"28","year":"2025","journal-title":"iScience"},{"key":"2026070108501007000_2025.12.11.693723v2.75","doi-asserted-by":"crossref","first-page":"68758","DOI":"10.18632\/oncotarget.20213","article-title":"Novel SOX17 frameshift mutations in endometrial cancer are functionally distinct from recurrent missense mutations","volume":"8","year":"2017","journal-title":"Oncotarget"},{"key":"2026070108501007000_2025.12.11.693723v2.76","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1038\/s41467-018-06652-w","article-title":"SOX17 regulates uterine epithelial\u2013stromal cross-talk acting via a distal enhancer upstream of Ihh","volume":"9","year":"2018","journal-title":"Nat Commun"},{"key":"2026070108501007000_2025.12.11.693723v2.77","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.03.008"},{"key":"2026070108501007000_2025.12.11.693723v2.78","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1722617115"},{"key":"2026070108501007000_2025.12.11.693723v2.79","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12582"},{"key":"2026070108501007000_2025.12.11.693723v2.80","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"2026070108501007000_2025.12.11.693723v2.81","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09320-9"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2025.12.11.693723","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:50:29Z","timestamp":1782921029000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2025.12.11.693723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":81,"URL":"https:\/\/doi.org\/10.64898\/2025.12.11.693723","relation":{},"subject":[],"published":{"date-parts":[[2025,12,15]]},"subtype":"preprint"}}