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A Role for the Transducer of the Hippo Pathway, TAZ, in the Development

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A Role for the Transducer of the Hippo Pathway, TAZ, in the Development Modern Pathology (2015) 28, 1492–1503 1492 © 2015 USCAP, Inc All rights reserved 0893-3952/15 $32.00 A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer Laura Romero-Pérez1, Pablo Garcia-Sanz2,3, Alba Mota2,3, Susanna Leskelä4, Marta Hergueta-Redondo2, Juan Díaz-Martín1, M Ángeles López-García1, M Ángeles Castilla1, Ángel Martínez-Ramírez5, Robert A Soslow6, Xavier Matias-Guiu7, Gema Moreno-Bueno2,3 and Jose Palacios1,4 1Department of Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/ CSIC/Universidad de Sevilla, Sevilla, Spain; 2Department of Biochemistry, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPAZ, Madrid, Spain; 3Translational Research Laboratory, MD Anderson International Foundation, Madrid, Spain; 4Department of Pathology, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Universidad de Alcalá, Madrid, Spain; 5Department of Molecular Cytogenetics, MD Anderson Cancer Center, Madrid, Spain; 6Department of Pathology, Memorial Sloan-Kettering Center, Memorial Hospital, New York, NY, USA and 7Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer. Modern Pathology (2015) 28, 1492–1503; doi:10.1038/modpathol.2015.102; published online 18 September 2015 In developed countries, endometrial carcinoma is clinical, pathological, and molecular features, the most common malignant tumor of the female endometrial carcinoma can be classified into at least genital tract.1 On the basis of epidemiological, two main categories:2 type I estrogen-dependent carcinomas that account for 80–85% of cases and Correspondence: Dr G Moreno-Bueno, PhD, Department of that are typically represented by low-grade (grade 1 Biochemistry, Universidad Autónoma de Madrid (UAM), Instituto and 2) endometrioid carcinomas, and type II endo- de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Calle metrial carcinomas that are not estrogen dependent Arturo Duperier, 4, Madrid 28029, Spain or Dr J Palacios, MD, PhD, Department of Pathology, Hospital Universitario Ramón y and that are mainly represented by a serous subtype Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), but also by other high-grade histological tumors like Universidad de Alcalá, Carretera de Colmenar Viejo, km. 9,100, clear cell or undifferentiated carcinomas.2 Madrid 28034, Spain. In endometrial carcinoma, the epithelial to E-mail: [email protected] or [email protected] mesenchymal transition has been associated with Received 7 May 2015; revised 21 July 2015; accepted 23 July 2015; – published online 18 September 2015 high-grade and aggressive features.3 6 Epithelial to www.modernpathology.org TAZ in endometrial cancer L Romero-Pérez et al 1493 mesenchymal transition is a key developmental Although TAZ and YAP have been associated to program by which polarized epithelial cells convert several types of cancer, their role in endometrial into motile mesenchymal ones, and it is a process that carcinoma is still unknown. To gain insight into a is activated during cancer invasion and metastasis.7 possible role of TAZ in endometrial carcinoma, we The epithelial to mesenchymal transition is studied the expression of TAZ and other epithelial to coordinated by a network of transcription factors that mesenchymal transition regulators in a series of 143 regulate the expression of proteins involved in cell endometrial carcinoma and endometrial carcinosar- polarity, cell-cell contacts, cytoskeletal structure, coma samples. Enhanced TAZ protein expression and extracellular matrix degradation.8 The loss of was observed in high-grade endometrial tumors and E-cadherin expression is a crucial event in epithelial this increase was associated to Scribble delocaliza- to mesenchymal transition and indeed, transcription tion. To further study the role of TAZ in endometrial factors associated to epithelial to mesenchymal carcinoma, we overexpressed and silenced this transition can be grouped according to their ability protein in endometrial cancer cell lines, demonstrat- to directly or indirectly repress E-cadherin.9 Among ing that increased TAZ expression is associated the direct repressors, we can find zinc finger proteins with cell motility, invasiveness, and tumor growth. like SNAIL1, SNAIL2, ZEB1 (TCF8), ZEB2 (SIP1), and Finally, we found that TAZ expression is associated the bHLH factor E47 (TCF3) or KLF8. By contrast, with molecular features of epithelial to mesenchymal indirect repressors include TWIST bHLH proteins or transition in endometrial cell lines and tumors. E22.8 In addition, the epithelial to mesenchymal transition program is closely linked to the acquisition of stem cell properties in other tumor cells, as defined Materials and methods by the acquisition of the CD44high/CD24low phenotype, in vitro self-renewal and in vivo tumor initiation Tumor Samples capacities.7,10 The epithelial to mesenchymal transi- In this study, we analyzed 143 formalin-fixed paraffin- tion has also been implicated in the dissemination of embedded samples from 56 grade 1-2 (low grade) and primary tumors owing to invasion or intravasation, 14 grade 3 (high grade) endometrioid endometrial as well as to the generation of distant tumors by carcinomas, 26 endometrial serous carcinomas, 21 migrating cancer stem cells.11 undifferentiated endometrial carcinomas, and 26 The Hippo pathway has been implicated in endometrial carcinosarcomas.3,4,21 We also analyzed epithelial to mesenchymal transition and stemness,12 33 frozen samples of 17 low-grade endometrioid and it is a pathway that coordinates cell proliferation, endometrial carcinomas and 16 endometrial carcino- apoptosis, and differentiation associated with the sarcomas.21 Histological typing of all the samples was regulation of organ development and regeneration.13 performed according to the World Health Organization The pathway involves a conserved kinase cascade, (WHO) classification and the tissue samples were and the final transcriptional co-activators TAZ and obtained from the Departments of Pathology at the YAP have been implicated in tissue homeostasis and Hospital Universitario Virgen del Rocío (Sevilla, the control of organ size through tissue-specific stem Spain), Memorial Sloan-Kettering Cancer Center cell regulation.14 Dysregulation of the Hippo pathway (New York, USA), and Hospital Universitari Arnau is correlated with epithelial to mesenchymal transition de Vilanova (IRBLLEIDA, Lleida, Spain). Representa- and cancer development, mainly driven by TAZ and tive areas of these samples were selected to set up six YAP.15 These two DNA-binding proteins are normally different tissue microarrays,22 and a summary of the repressed by Mst2 and Lats2 phosphorylation,16,17 or relevant clinicopathological features is provided in they are regulated by the expression and location of Supplementary Table 1. This study was performed the cell polarity protein Scribble.18 TAZ/YAP and following the standard Spanish ethical regulations epithelial to mesenchymal transition are thought to (Ley de Investigación Orgánica Biomédica, 14 July maintain a bidirectional relationship, whereby the loss 2007) and it was approved by the ethic committees of of polarity and cell contacts (key events during the each institution involved. epithelial to mesenchymal transition process) induces the activation of both factors, which in turn participate 19 in the epithelial to mesenchymal transition program. Immunohistochemistry and Fluorescence In Situ Specifically, the transcriptional co-activator TAZ Hybridization (WWTR1) has been associated with the loss of E-cadherin function in breast cancer.18 and it also Tissue microarray sections were assessed by induces the expression of transcription factors asso- immunohistochemistry and fluorescence in situ ciated to epithelial to mesenchymal transition like hybridization. Immunohistochemistry was ZEB1 in retinal pigment epithelial cells.20 Moreover,
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