title: Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma.
abstract: Epithelial to mesenchymal transition is thought to be implicated in tumor invasion and metastasis. To investigate its role in myometrial invasion, samples from 42 stage I (confined to the corpus) endometrioid endometrial carcinomas were analyzed. All E-cadherin repressors (SNAI1, SNAI2 (SLUG), ZEB1, HMGA2, and TWIST1) had a higher expression in endometrioid endometrial carcinomas than in normal endometrium (P < .0001), whereas CDH1 (E-cadherin gene) tended to be lower. In comparison with nonmyoinvasive (stage IA) tumors, those with deep myometrial invasion (stage IC) had increased messenger RNA expression of SLUG, ZEB1, and HMGA2 (P < .001). Furthermore, samples from the myoinvasive front of deeply invasive tumors had higher levels of SLUG, ZEB1, and HMGA2 than the corresponding superficial samples. Immunohistochemical analysis of these cases revealed that the decrease in E-cadherin was concordant with an increase in Snail and Twist protein expression. Trying to induce epithelial to mesenchymal transition in endometrioid endometrial carcinomas, we initially produced persistent activation of this pathway in Ishikawa cells. The cell line was infected with lentiviruses carrying the V600E mutation of BRAF, inducing loss of β-catenin, E-cadherin, and cytokeratin and increase in vimentin and Snail. These changes were mediated by ERK1/2 phosphorylation, which was also increased at the myoinvasive front. Furthermore, MEK1/2 inhibitor UO126 reversed the mesenchymal phenotype. Our findings suggest that epithelial to mesenchymal transition regulators are implicated in myometrial invasion of endometrioid endometrial carcinoma and may be potential therapeutic targets through the MAPK/ERK pathway.
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08041 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Montserrat
authors.forename: Ana
authors.initials: A
authors.lastname: Mozos
authors.forename: David
authors.initials: D
authors.lastname: Llobet
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.forename: Cristina
authors.initials: C
authors.lastname: Pons
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D051176:beta Catenin