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

Abstract

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 (2015Pathology ( ) 28, 1492Pathology ( -1503 doi:10.1038/modpathol.2015 published online 18 September 2015 In developed countries, endometrial carcinoma is the most common malignant tumor of the female genital tract. 1 On the basis of epidemiological, clinical, pathological, and molecular features, endometrial carcinoma can be classified into at least two main categories: 2 type I estrogen-dependent carcinomas that account for 80-85% of cases and that are typically represented by low-grade (grade 1 and 2) endometrioid carcinomas, and type II endometrial carcinomas that are not estrogen dependent and that are mainly represented by a serous subtype but also by other high-grade histological tumors like clear cell or undifferentiated carcinomas. 2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas

“…Table 1. The pathological and immunohistochemical features of 10 cases have been previously reported in part [5]. The diagnosis of undifferentiated carcinoma was based not only on conventional morphological features but also on the characteristic immunohistochemical pattern reported previously; i.e., absence of E-cadherin expression together with ZEB1 nuclear immunoreaction (see Figures 1 and 2) [8].…”

“…Defining features include: a) monotonous medium or large-sized cells; b) diffuse pattern of growth; and c) a lack of appreciable glandular, papillary, squamous, or neuroendocrine differentiation [1, 3, 4]. Undifferentiated endometrial carcinoma lacks expression of epithelial markers, such as keratins, E-cadherin, and mir-200 but express ZEB-1, a well-known repressor of E-cadherin [5]. In addition, undifferentiated endometrial carcinoma is frequently associated with mismatch repair deficiency [5].…”

“…Undifferentiated endometrial carcinoma lacks expression of epithelial markers, such as keratins, E-cadherin, and mir-200 but express ZEB-1, a well-known repressor of E-cadherin [5]. In addition, undifferentiated endometrial carcinoma is frequently associated with mismatch repair deficiency [5]. …”

Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer

“…Furthermore, removal of the tumor suppressor AMOT/Merlin from the TJ position induces TEAD/AREG via the Hippo/YAP pathway and then enhances the migration, invasion and proliferation of cancer cells18. The development and progression of endometrial cancer are also attributed to the Hippo/YAP pathway20.…”

“…The Hippo/YAP pathway is a key regulator of organ size and tissue homeostasis and is dysregulated in many human cancers19. The development and progression of endometrial cancer are in part attributed to the Hippo/YAP pathway20. On the other hand, glucose starvation induces activation of pYAP via AMP-dependent protein kinase (AMPK) and the activation of pYAP prevents transcription of TEAD21.…”