{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:28:45Z","timestamp":1785796125382,"version":"3.56.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIH","award":["CA143931"],"award-info":[{"award-number":["CA143931"]}]},{"name":"NIH","award":["CA143931"],"award-info":[{"award-number":["CA143931"]}]},{"name":"Translational Research Fund"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In type 1 endometrial cancer, unopposed estrogen stimulation is thought to lead to endometrial hyperplasia which precedes malignant progression. Recent data from our group and others suggest that ALDH activity mediates stemness in endometrial cancer, but while aldehyde dehydrogenase 1 (ALDH1) has been suggested as a putative cancer stem cell marker in several cancer types, its clinical and prognostic value in endometrial cancer remains debated. The aim of this study was to investigate the clinical value of ALDH1 expression in endometrial hyperplasia and to determine its ability to predict progression to endometrial cancer. Interrogation of the TCGA database revealed upregulation of several isoforms in endometrial cancer, of which the ALDH1 isoforms collectively constituted the largest group. To translate its expression, a tissue microarray was previously constructed which contained a wide sampling of benign and malignant endometrial samples. The array contained a metachronous cohort of samples from individuals who either developed or did not develop\u00a0endometrial cancer. Immunohistochemical staining was used to determine the intensity and frequency of ALDH1 expression. While benign proliferative and secretory endometrium showed very low levels of ALDH1, slightly higher expression was observed within the stratum basalis. In disease progression, cytoplasmic ALDH1 expression showed a step-wise increase between endometrial hyperplasia, atypical hyperplasia, and endometrial cancer. ALDH1 was also shown to be an early predictor of EC development, suggesting that it can serve as an independent prognostic indicator of patients with endometrial hyperplasia with or without atypia who would progress to cancer (<jats:italic>p<\/jats:italic>\u2009=\u20090.012).<\/jats:p>","DOI":"10.1038\/s41598-021-90570-3","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T10:06:06Z","timestamp":1623060366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["ALDH1 expression predicts progression of premalignant lesions to cancer in Type I endometrial carcinomas"],"prefix":"10.1038","volume":"11","author":[{"given":"Vei","family":"Mah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahya","family":"Elshimali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neda A.","family":"Moatamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamar P.","family":"Uzzell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Tsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Schettler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hania","family":"Shakeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhuri","family":"Wadehra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"90570_CR1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1097\/GCO.0000000000000338","volume":"29","author":"YC Lee","year":"2017","unstructured":"Lee, Y. C., Lheureux, S. & Oza, A. M. Treatment strategies for endometrial cancer: current practice and perspective. Curr. Opin. Obstet. Gynecol. 29, 47\u201358 (2017).","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"90570_CR2","volume-title":"Tumours of the Uterine Corpus: Endometrial Tumors and Precursor","author":"R Zaino","year":"2014","unstructured":"Zaino, R. et al. Tumours of the Uterine Corpus: Endometrial Tumors and Precursor 4th edn. (International Agency for Research on Cancer, 2014).","edition":"4"},{"key":"90570_CR3","first-page":"232","volume":"23","author":"PA Sanderson","year":"2016","unstructured":"Sanderson, P. A., Critchley, H. O. D., Williams, A. R. W., Arends, M. J. & Saunders, P. T. K. New concepts for an old problem: the diagnosis of endometrial hyperplasia. Hum. Reprod. Update 23, 232\u2013254 (2016).","journal-title":"Hum. Reprod. Update"},{"key":"90570_CR4","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1038\/nm.4409","volume":"23","author":"E Batlle","year":"2017","unstructured":"Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124\u20131134 (2017).","journal-title":"Nat. Med."},{"key":"90570_CR5","doi-asserted-by":"publisher","first-page":"14759","DOI":"10.1002\/jcp.28271","volume":"234","author":"M Akbarzadeh","year":"2019","unstructured":"Akbarzadeh, M. et al. Current approaches in identification and isolation of cancer stem cells. J. Cell. Physiol. 234, 14759\u201314772 (2019).","journal-title":"J. Cell. Physiol."},{"key":"90570_CR6","doi-asserted-by":"publisher","first-page":"5793","DOI":"10.1038\/onc.2017.142","volume":"36","author":"MH Kiyohara","year":"2017","unstructured":"Kiyohara, M. H. et al. EMP2 is a novel therapeutic target for endometrial cancer stem cells. Oncogene 36, 5793\u20135807 (2017).","journal-title":"Oncogene"},{"key":"90570_CR7","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1111\/cas.12999","volume":"107","author":"S Tahara","year":"2016","unstructured":"Tahara, S. et al. S100A4 accelerates the proliferation and invasion of endometrioid carcinoma and is associated with the \u201cMELF\u201d pattern. Cancer Sci. 107, 1345\u20131352 (2016).","journal-title":"Cancer Sci."},{"key":"90570_CR8","doi-asserted-by":"publisher","first-page":"e0145164","DOI":"10.1371\/journal.pone.0145164","volume":"10","author":"J Chen","year":"2015","unstructured":"Chen, J. et al. Prognostic value of cancer stem cell marker ALDH1 expression in colorectal cancer: a systematic review and meta-analysis. PLoS ONE 10, e0145164 (2015).","journal-title":"PLoS ONE"},{"key":"90570_CR9","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1002\/jso.23792","volume":"111","author":"SY Oh","year":"2015","unstructured":"Oh, S. Y. et al. ALDH1 is a prognostic factor for patients treated with neoadjuvant chemoradiotherapy and radical resection for stage III rectal cancer. J. Surg. Oncol. 111, 243\u2013247 (2015).","journal-title":"J. Surg. Oncol."},{"key":"90570_CR10","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.canep.2015.03.003","volume":"39","author":"N Xu","year":"2015","unstructured":"Xu, N. et al. Aldehyde dehydrogenase 1 (ALDH1) expression is associated with a poor prognosis of bladder cancer. Cancer Epidemiol. 39, 375\u2013381 (2015).","journal-title":"Cancer Epidemiol."},{"key":"90570_CR11","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1097\/PAT.0000000000000325","volume":"47","author":"A Matsika","year":"2015","unstructured":"Matsika, A. et al. Cancer stem cell markers in prostate cancer: an immunohistochemical study of ALDH1, SOX2 and EZH2. Pathology 47, 622\u2013628 (2015).","journal-title":"Pathology"},{"key":"90570_CR12","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1007\/s12032-014-0864-0","volume":"31","author":"Y Zhong","year":"2014","unstructured":"Zhong, Y. et al. ALDH1 is a better clinical indicator for relapse of invasive ductal breast cancer than the CD44+\/CD24\u2212 phenotype. Med. Oncol. (Northwood Lond. Engl.) 31, 864 (2014).","journal-title":"Med. Oncol. (Northwood Lond. Engl.)"},{"key":"90570_CR13","doi-asserted-by":"publisher","first-page":"7491","DOI":"10.7314\/APJCP.2015.16.17.7491","volume":"16","author":"SF Mansour","year":"2015","unstructured":"Mansour, S. F. & Atwa, M. M. Clinicopathological significance of CD133 and ALDH1 cancer stem cell marker expression in invasive ductal breast carcinoma. Asian Pac. J. Cancer Prev. APJCP 16, 7491\u20137496 (2015).","journal-title":"Asian Pac. J. Cancer Prev. APJCP"},{"key":"90570_CR14","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","volume":"6","author":"J Gao","year":"2013","unstructured":"Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).","journal-title":"Sci. Signal"},{"key":"90570_CR15","doi-asserted-by":"publisher","first-page":"4718","DOI":"10.1002\/cncr.25259","volume":"116","author":"O Habeeb","year":"2010","unstructured":"Habeeb, O. et al. Epithelial membrane protein-2 expression is an early predictor of endometrial cancer development. Cancer 116, 4718\u20134726 (2010).","journal-title":"Cancer"},{"key":"90570_CR16","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s00404-019-05103-1","volume":"299","author":"A Raffone","year":"2019","unstructured":"Raffone, A. et al. Endometrial hyperplasia and progression to cancer: Which classification system stratifies the risk better? A systematic review and meta-analysis. Arch. Gynecol. Obst. 299, 1233\u20131242 (2019).","journal-title":"Arch. Gynecol. Obst."},{"key":"90570_CR17","doi-asserted-by":"publisher","first-page":"3904645","DOI":"10.1155\/2019\/3904645","volume":"2019","author":"G Vassalli","year":"2019","unstructured":"Vassalli, G. Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells. Stem Cells Int. 2019, 3904645 (2019).","journal-title":"Stem Cells Int."},{"key":"90570_CR18","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","volume":"173","author":"KA Hoadley","year":"2018","unstructured":"Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291\u2013304 (2018).","journal-title":"Cell"},{"key":"90570_CR19","first-page":"931","volume":"16","author":"A L\u00f3pez-Gonz\u00e1lez","year":"2014","unstructured":"L\u00f3pez-Gonz\u00e1lez, A., Salas, C., Provencio, M., C\u00f3rdoba, M. & Gamallo, C. Aldehyde dehydrogenases in early stage lung cancer: nuclear expression. Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mexico 16, 931\u2013934 (2014).","journal-title":"Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mexico"},{"key":"90570_CR20","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1111\/j.1442-2050.2011.01279.x","volume":"25","author":"Y Wang","year":"2012","unstructured":"Wang, Y. et al. Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China. Dis. Esophagus off. J. Int. Soc. Dis. Esophagus 25, 560\u2013565 (2012).","journal-title":"Dis. Esophagus off. J. Int. Soc. Dis. Esophagus"},{"key":"90570_CR21","doi-asserted-by":"publisher","first-page":"43","DOI":"10.21037\/sci.2018.11.03","volume":"5","author":"JS Lee","year":"2018","unstructured":"Lee, J. S. & Kim, W. G. Potential protective effect of ALDH-1 stromal expression against early recurrence of operable breast cancers. Stem Cell Investig. 5, 43 (2018).","journal-title":"Stem Cell Investig."},{"key":"90570_CR22","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s12672-015-0223-4","volume":"6","author":"MJ Pineda","year":"2015","unstructured":"Pineda, M. J., Lu, Z., Cao, D. & Kim, J. J. Influence of cancer-associated endometrial stromal cells on hormone-driven endometrial tumor growth. Hormones Cancer 6, 131\u2013141 (2015).","journal-title":"Hormones Cancer"},{"key":"90570_CR23","doi-asserted-by":"publisher","first-page":"107","DOI":"10.5114\/pm.2017.70589","volume":"16","author":"K Sobczuk","year":"2017","unstructured":"Sobczuk, K. & Sobczuk, A. New classification system of endometrial hyperplasia WHO 2014 and its clinical implications. Przeglad Menopauzalny Menopause Rev. 16, 107\u2013111 (2017).","journal-title":"Przeglad Menopauzalny Menopause Rev."},{"key":"90570_CR24","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.canlet.2015.08.018","volume":"369","author":"X Xu","year":"2015","unstructured":"Xu, X. et al. Aldehyde dehydrogenases and cancer stem cells. Cancer Lett. 369, 50\u201357 (2015).","journal-title":"Cancer Lett."},{"key":"90570_CR25","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1124\/pr.111.005538","volume":"64","author":"V Koppaka","year":"2012","unstructured":"Koppaka, V. et al. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol. Rev. 64, 520\u2013539 (2012).","journal-title":"Pharmacol. Rev."},{"key":"90570_CR26","doi-asserted-by":"publisher","first-page":"321","DOI":"10.3892\/ol.2016.5379","volume":"13","author":"U Habiba","year":"2017","unstructured":"Habiba, U. et al. ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia. Oncol. Lett. 13, 321\u2013328 (2017).","journal-title":"Oncol. Lett."},{"key":"90570_CR27","first-page":"755","volume":"42","author":"AA Abdulmajeed","year":"2013","unstructured":"Abdulmajeed, A. A., Dalley, A. J. & Farah, C. S. Putative cancer stem cell marker expression in oral epithelial dysplasia and squamous cell carcinoma. J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol. 42, 755\u2013760 (2013).","journal-title":"J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol."},{"key":"90570_CR28","doi-asserted-by":"publisher","first-page":"503047","DOI":"10.1155\/2013\/503047","volume":"2013","author":"M-E Roehrich","year":"2013","unstructured":"Roehrich, M.-E., Spicher, A., Milano, G. & Vassalli, G. Characterization of cardiac-resident progenitor cells expressing high aldehyde dehydrogenase activity. Biomed. Res. Int. 2013, 503047\u2013503047 (2013).","journal-title":"Biomed. Res. Int."},{"key":"90570_CR29","doi-asserted-by":"publisher","first-page":"11018","DOI":"10.18632\/oncotarget.6920","volume":"7","author":"H Tomita","year":"2016","unstructured":"Tomita, H., Tanaka, K., Tanaka, T. & Hara, A. Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget 7, 11018\u201311032 (2016).","journal-title":"Oncotarget"},{"key":"90570_CR30","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1002\/stem.613","volume":"29","author":"AE Balber","year":"2011","unstructured":"Balber, A. E. Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine. Stem Cells (Dayton, Ohio) 29, 570\u2013575 (2011).","journal-title":"Stem Cells (Dayton, Ohio)"},{"key":"90570_CR31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.stemcr.2013.11.009","volume":"2","author":"S Liu","year":"2014","unstructured":"Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2, 78\u201391 (2014).","journal-title":"Stem Cell Rep."},{"key":"90570_CR32","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.cell.2005.10.026","volume":"123","author":"DJ Laird","year":"2005","unstructured":"Laird, D. J., De Tomaso, A. W. & Weissman, I. L. Stem cells are units of natural selection in a colonial ascidian. Cell 123, 1351\u20131360 (2005).","journal-title":"Cell"},{"key":"90570_CR33","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.ceb.2017.05.006","volume":"48","author":"M Reina-Campos","year":"2017","unstructured":"Reina-Campos, M., Moscat, J. & Diaz-Meco, M. Metabolism shapes the tumor microenvironment. Curr. Opin. Cell Biol. 48, 47\u201353 (2017).","journal-title":"Curr. Opin. Cell Biol."},{"key":"90570_CR34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.17.00121","volume":"2","author":"RJ Torphy","year":"2018","unstructured":"Torphy, R. J. et al. Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precis. Oncol. 2, 1\u201312 (2018).","journal-title":"JCO Precis. Oncol."},{"key":"90570_CR35","doi-asserted-by":"publisher","first-page":"5305","DOI":"10.1038\/s41388-018-0294-0","volume":"37","author":"Z Al Shareef","year":"2018","unstructured":"Al Shareef, Z. et al. Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1. Oncogene 37, 5305\u20135324 (2018).","journal-title":"Oncogene"},{"key":"90570_CR36","doi-asserted-by":"publisher","first-page":"26789","DOI":"10.18632\/oncotarget.4628","volume":"6","author":"N Bednarz-Knoll","year":"2015","unstructured":"Bednarz-Knoll, N. et al. Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression. Oncotarget 6, 26789\u201326803 (2015).","journal-title":"Oncotarget"},{"key":"90570_CR37","first-page":"2943","volume":"62","author":"I Rabinovich","year":"2018","unstructured":"Rabinovich, I. et al. Cancer stem cell markers ALDH1 and CD44+\/CD24- phenotype and their prognosis impact in invasive ductal carcinoma. Eur. J. histochem. EJH 62, 2943 (2018).","journal-title":"Eur. J. histochem. EJH"},{"key":"90570_CR38","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1111\/j.1349-7006.2011.01864.x","volume":"102","author":"N Rahadiani","year":"2011","unstructured":"Rahadiani, N. et al. Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications. Cancer Sci. 102, 903\u2013908 (2011).","journal-title":"Cancer Sci."},{"key":"90570_CR39","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s10549-016-3738-7","volume":"156","author":"K Kida","year":"2016","unstructured":"Kida, K. et al. Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype. Breast Cancer Res. Treat. 156, 261\u2013269 (2016).","journal-title":"Breast Cancer Res. Treat."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90570-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90570-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90570-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T10:04:49Z","timestamp":1725185089000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90570-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,7]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["90570"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-90570-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,7]]},"assertion":[{"value":"30 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11949"}}