The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells

Cordenonsi, Michelangelo; Zanconato, Francesca; Azzolin, Luca; Forcato, Mattia; Rosato, Antonio; Frasson, Chiara; Inui, Masafumi; Montagner, Marco; Parenti, Anna; Poletti, Alessandro; Daidone, Maria Grazia; Dupont, Sirio; Basso, Giuseppe; Bicciato, Silvio; Piccolo, Stefano

doi:10.1016/j.cell.2011.09.048

Cited by 1,155 publications

(1,421 citation statements)

References 70 publications

(71 reference statements)

Supporting

Mentioning

1,293

Contrasting

Unclassified

Order By: Relevance

“…15 These two DNA-binding proteins are normally repressed by Mst2 and Lats2 phosphorylation, 16,17 or they are regulated by the expression and location of the cell polarity protein Scribble. 18 TAZ/YAP and epithelial to mesenchymal transition are thought to maintain a bidirectional relationship, whereby the loss of polarity and cell contacts (key events during the epithelial to mesenchymal transition process) induces the activation of both factors, which in turn participate in the epithelial to mesenchymal transition program. 19 Specifically, the transcriptional co-activator TAZ (WWTR1) has been associated with the loss of E-cadherin function in breast cancer.…”

mentioning

confidence: 99%

“…19 Specifically, the transcriptional co-activator TAZ (WWTR1) has been associated with the loss of E-cadherin function in breast cancer. 18 and it also induces the expression of transcription factors associated to epithelial to mesenchymal transition like ZEB1 in retinal pigment epithelial cells. 20 Moreover, it has been shown that TAZ may confer cancer stem cell properties to breast cancer cells, 18 and it is coupled to the loss of polarity in epithelial cells through the membrane delocalization of Scribble during epithelial to mesenchymal transition.…”

mentioning

confidence: 99%

“…18 and it also induces the expression of transcription factors associated to epithelial to mesenchymal transition like ZEB1 in retinal pigment epithelial cells. 20 Moreover, it has been shown that TAZ may confer cancer stem cell properties to breast cancer cells, 18 and it is coupled to the loss of polarity in epithelial cells through the membrane delocalization of Scribble during epithelial to mesenchymal transition. 18 Although TAZ and YAP have been associated to several types of cancer, their role in endometrial carcinoma is still unknown.…”

mentioning

confidence: 99%

“…20 Moreover, it has been shown that TAZ may confer cancer stem cell properties to breast cancer cells, 18 and it is coupled to the loss of polarity in epithelial cells through the membrane delocalization of Scribble during epithelial to mesenchymal transition. 18 Although TAZ and YAP have been associated to several types of cancer, their role in endometrial carcinoma is still unknown. To gain insight into a possible role of TAZ in endometrial carcinoma, we studied the expression of TAZ and other epithelial to mesenchymal transition regulators in a series of 143 endometrial carcinoma and endometrial carcinosarcoma samples.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…18,19 The COSMIC data base shows an intriguing upregulation of YAP and TAZ factors in endocrine cancers (thyroid, breast, ovary and prostate). 20,21 The Drosophila homologue of YAP and TAZ is Yorkie whose overactivation also results in overgrowth. 22 Cell death during metamorphosis is considered a suitable model to investigate the basic mechanisms of tumor growth regulation by mammalian steroids.…”

mentioning

confidence: 99%

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

2015

View full text Add to dashboard Cite

The active form of the Drosophila steroid hormone ecdysone, 20-hydroxyecdysone (20E), binds the heterodimer EcR/USP nuclear receptor to regulate target genes that elicit proliferation, cell death and differentiation during insect development. Although the 20E effects are relatively well known, the physiological relevance of its receptors remains poorly understood. We show here that the prothoracic gland (PG), the major steroid-producing organ of insect larvae, requires EcR and USP to survive in a critical period previous to metamorphosis, and that this requirement is 20E-independent. The cell death induced by the downregulation of these receptors involves the activation of the JNK-encoding basket gene and it can be rescued by upregulating EcR isoforms which are unable to respond to 20E. Also, while PG cell death prevents ecdysone production, blocking hormone synthesis or secretion in normal PG does not lead to cell death, demonstrating further the ecdysone-independent nature of the receptor-deprivation cell death. In contrast to PG cells, wing disc or salivary glands cells do not require these receptors for survival, revealing their cell and developmental time specificity. Exploring the potential use of this feature of steroid receptors in cancer, we assayed tumor overgrowth induced by altered yorkie signaling. This overgrowth is suppressed by EcR downregulation in PG, but not in wing disc, cells. The mechanism of all these cell death features is based on the transcriptional regulation of reaper. These novel and context-dependent functional properties for EcR and USP receptors may help to understand the heterogeneous responses to steroid-based therapies in human pathologies. Steroid hormones control multiple biological processes and, consequently, their faulty regulation underlies many pathologies. 1,2 The main Drosophila steroid hormone, ecdysone, is synthesized in the larval prothoracic gland (PG) using dietary sterols and cytochrome P450 enzymes. 3 Following its pulsated secretion into the hemolymph, peripheral tissues convert ecdysone into biologically active 20-hydroxyecdysone (20E) to control larval molting and metamorphosis. 4 The 20E signal is transduced by heterodimers of two nuclear receptors, ecdysone receptor (EcR) and Ultraspiracle (USP). 5 USP exhibits a single form throughout development. By contrast, EcR encodes three protein isoforms (EcRA, EcRB1 and EcRB2). These show common DNA-and hormone-binding domains but different N-termini although all of them can heterodimerize USP. 6,7 Each EcR isoform is hypothesized to have specific functions based on their distinct spatial and temporal patterns and N-termini. [8][9][10] EcR and USP DNA-binding domains recognize ecdysone response sequences which are short palindromes. 11 Like its vertebrate counterparts, 12 the ligand-EcR/USP complex activates transcription, whereas the unliganded receptor act as a repressor. [13][14][15] The in vivo validation of repressor activities for unliganded complexes, however, is mostly indirect. For example, EcR or USP loss...

show abstract

The FZD7‐TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma

et al. 2019

View full text Add to dashboard Cite

Frizzled family receptor 7 ( FZD 7 ), a Wnt signaling receptor, is associated with the maintenance of stem cell properties and cancer progression. FZD 7 has emerged as a potential therapeutic target because it is capable of transducing both canonical and noncanonical Wnt signals. In this study, we investigated the regulatory pathway downstream of FZD 7 and its functional roles. We found that FZD 7 expression was crucial to the maintenance of the mesenchymal phenotype, anoikis resistance, and spheroid and tumor formation in ovarian cancer (OC). We identified TWIST 1 as the crucial downstream effector of the FZD 7 pathway. TWIST 1 , a basic helix loop helix transcription factor, is known to associate with mesenchymal and cancer stem cell phenotypes. Manipulating TWIST 1 expression mimicked the functional consequences observed in the FZD 7 model, and overexpression of TWIST 1 partially rescued the functional phenotypes abolished by FZD 7 knockdown. We further proved that FZD 7 regulated TWIST 1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST 1 proximal promoter. We also identified that the FZD 7 ‐ TWIST 1 axis regulates the expression of BCL 2 , a gene that controls apoptosis. Identification of this FZD 7 ‐ TWIST 1 ‐ BCL 2 pathway reaffirms the mechanism of anoikis resistance in OC. We subsequently showed that the FZD 7 ‐ TWIST 1 axis can be targeted by using a small molecule inhibitor of porcupine, an enzyme essential for secretion and functional activation of Wnts. In conclusion, our results identified that the FZD 7 ‐ TWIST 1 axis is important for tumorigenesis and anoikis resistance, and therapeutic inhibition results in cell death in OCs.

show abstract

The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells

Cited by 1,155 publications

References 70 publications

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

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

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

The FZD7‐TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma

Contact Info

Product

Resources

About