ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma Journal Article

  

Authors:	Romero-Pérez, L.; López-García, M. Á; Díaz-Martín, J.; Biscuola, M.; Castilla, M. A.; Tafe, L. J.; Garg, K.; Oliva, E.; Matias-Guiu, X.; Soslow, R. A.; Palacios, J.
Article 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. © 2013 USCAP, Inc.
Keywords:	e-cadherin; zeb1; mir-200s; undifferentiated endometrial carcinoma
Journal Title:	Modern Pathology
Volume:	26
Issue:	11
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2013-11-01
Start Page:	1514
End Page:	1524
Language:	English
DOI:	10.1038/modpathol.2013.93
PROVIDER:	scopus
PUBMED:	23743934
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84887067821&partnerID=40&md5=fffdd4bb1b641fe7c8019079371e0a25
Notes:	--- - "Export Date: 2 December 2013" - "CODEN: MODPE" - "Source: Scopus"

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