The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene

Zhang, X; George, Joshy; Deb, S; Degoutin, Joffrey L.; Takano, Elena A.; Fox, Stephen B.; Bowtell, David D.L.; Harvey, Kieran F.

doi:10.1038/onc.2011.8

Cited by 276 publications

(250 citation statements)

References 49 publications

Supporting

Mentioning

235

Contrasting

Unclassified

Order By: Relevance

“…Huang et al reported that knockdown of YAP significantly increased EGFRI erlotinib sensitivity in ovarian cancer cell lines that express little or no TAZ (21). In addition, knockdown of YAP in ovarian cancer cell lines that express both YAP and TAZ only led to a very moderate effect on cancer cell growth or drug sensitivity (22,23). Here, we have shown that knockdown of TAZ in breast cancer cell lines that express little or no YAP, such as BT-549 cells, increased EGFRI sensitivity; however, for breast cancer cell lines that express both YAP and TAZ, such as MDA-MB-231 cells, knockdown of TAZ may not help improve sensitivity of EGFRI treatment.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

et al. 2016

View full text Add to dashboard Cite

Abstract. Triple-negative breast cancer (TNBC) constitutes ~10-15% of breast cancer patients and represents an aggressive subtype with poor overall prognosis. TNBC is an important clinical challenge because it does not respond well to endocrine therapy and have a higher rate of early recurrence and distant metastasis following chemotherapy. Although it has been reported that the epidermal growth factor receptor (EGFR) was overexpressed in ~80% of TNBC, anti-EGFR therapy showed limited clinical benefit according to phase II studies. In this study, we first observed that knockdown of the transcriptional coactivator with PDZ-binding domain (TAZ) gene can regulate the sensitivity of TNBC cell lines to EGFR inhibitors (EGFRI) in a cell context-depended manner. Furthermore, in certain breast cancer cell lines the YES-associated protein, paralog of TAZ (YAP) expression can be upregulated by TAZ inhibition which leads to EGFRI resistance. These results suggest a specific inhibitor to TAZ/YAP combined with anti-EGFR therapy may prove effective and provide a reason why targeting EGFR showed limited clinical benefit in TNBC treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

et al. 2016

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

“…YAP, a mammalian homolog of Drosophila Yorkie), a key effector of this pathway, promotes EMT and cell motility in vitro (Overholtzer et al 2006;Zhao et al 2008a;Zhang et al 2009). Furthermore, abnormal YAP activity associates with poor survival of ovarian cancer patients significantly (Hall et al 2010;Zhang et al 2011b). These results drew our attention to investigate roles of the Hippo pathway in cell migration.…”

mentioning

confidence: 99%

The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary

Lin¹,

Yeh²,

Wang

et al. 2014

Genetics

View full text Add to dashboard Cite

The Hippo pathway is a key signaling cascade in controlling organ size. The core components of this pathway are two kinases, Hippo (Hpo) and Warts (Wts), and a transcriptional coactivator, Yorkie (Yki). Yes-associated protein (YAP, a Yki homolog in mammals) promotes epithelial-mesenchymal transition and cell migration in vitro. Here, we use border cells in the Drosophila ovary as a model to study Hippo pathway functions in cell migration in vivo. During oogenesis, polar cells secrete Unpaired (Upd), which activates JAK/STAT signaling of neighboring cells and specifies them into outer border cells. The outer border cells form a cluster with polar cells and undergo migration. We find that hpo and wts are required for migration of the border cell cluster. In outer border cells, overexpression of hpo disrupts polarization of the actin cytoskeleton and attenuates migration. In polar cells, knockdown of hpo and wts or overexpression of yki impairs border cell induction and disrupts migration. These manipulations in polar cells reduce JAK/STAT activity in outer border cells. Expression of upd-lacZ is increased and decreased in yki and hpo mutant polar cells, respectively. Furthermore, forced expression of upd in polar cells rescues defects of border cell induction and migration caused by wts knockdown. These results suggest that Yki negatively regulates border cell induction by inhibiting JAK/STAT signaling. Together, our data elucidate two distinct mechanisms of the Hippo pathway in controlling border cell migration: (1) in outer border cells, it regulates polarized distribution of the actin cytoskeleton; (2) in polar cells, it regulates upd expression to control border cell induction and migration.

show abstract

The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene

Cited by 276 publications

References 49 publications

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

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

The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary

Contact Info

Product

Resources

About