title: ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma.
abstract: Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (∼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.
authors.affiliation: Department of Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Romero-Pérez
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: López-García
authors.forename: Juan
authors.initials: J
authors.lastname: Díaz-Martín
authors.forename: Michele
authors.initials: M
authors.lastname: Biscuola
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Castilla
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Tafe
authors.forename: Karuna
authors.initials: K
authors.lastname: Garg
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.forename: José
authors.initials: J
authors.lastname: Palacios
mesh_terms: D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D015820:Cadherins / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000032:analysis*; D060787:Neoplasm Grading; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013030:Spain; D014157:Transcription Factors / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014481:United States; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1