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 (B33%) 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 epithelialto-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 420% 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.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

“…34 Hence, it would appear that TAZ is a potent activator of cell transformation and tumorigenesis. 35,36 On the basis of this evidence, and given the importance of epithelial to mesenchymal transition and stemness in the carcinogenesis of certain subtypes of endometrial tumors, 3,4 we analyzed TAZ expression in a series of 143 endometrial carcinoma samples. We found that TAZ expression was associated with high-grade endometrial tumors, mainly represented by undifferentiated endometrial carcinomas and endometrial carcinosarcomas.…”

“…3,4,21 We also analyzed 33 frozen samples of 17 low-grade endometrioid endometrial carcinomas and 16 endometrial carcinosarcomas. 21 Histological typing of all the samples was performed according to the World Health Organization (WHO) classification and the tissue samples were obtained from the Departments of Pathology at the Hospital Universitario Virgen del Rocío (Sevilla, Spain), Memorial Sloan-Kettering Cancer Center (New York, USA), and Hospital Universitari Arnau de Vilanova (IRBLLEIDA, Lleida, Spain).…”

“…2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to …”

“…2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to mesenchymal transition is a key developmental program by which polarized epithelial cells convert into motile mesenchymal ones, and it is a process that is activated during cancer invasion and metastasis. 7 The epithelial to mesenchymal transition is coordinated by a network of transcription factors that regulate the expression of proteins involved in cell polarity, cell-cell contacts, cytoskeletal structure, and extracellular matrix degradation.…”

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…ZEB1 overexpression and downregulation of miR-200s in these tumors was associated with absent or downregulated E-cadherin expression (Romero-Perez et al 2013). Upregulation of fascin, an actin binding protein, was recently suggested to represent an EMT like process in UECs and also contribute toward the invasive character of this aggressive EC subtype (Stewart & Crook 2015a).…”