Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways

Donninger, Howard; Bonome, Tomás; Radonovich, Michael F.; Pise-Masison, Cynthia A.; Brady, John; Shih, Joanna H.; Barrett, J. Carl; Birrer, Michael J.

doi:10.1038/sj.onc.1207959

Cited by 118 publications

(93 citation statements)

References 72 publications

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“…In this context, the ability of ET-1 to control the tumor-host interactions (6,(9)(10)(11), underlines its key role allowing close coordination in the cellular signaling network in ovarian cancer growth and progression. These findings complement and extend the analysis of gene expression profile of late-stage ovarian cancer whereby ET A R has been identified as a metastasis-associated gene (12). To characterize downstream mediators in ET-1-induced ovarian cancer invasion and metastasis, we focused on the role of ␤-arrestins, as scaffold proteins of GPCR, in the ␤-catenin signaling pathway.…”

mentioning

confidence: 91%

β-Arrestin links endothelin A receptor to β-catenin signaling to induce ovarian cancer cell invasion and metastasis

Rosanò¹,

Cianfrocca

Masi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

149

161

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The activation of endothelin-A receptor (ETAR) by endothelin-1 (ET-1) has a critical role in ovarian tumorigenesis and progression. To define the molecular mechanism in ET-1-induced tumor invasion and metastasis, we focused on ␤-arrestins as scaffold and signaling proteins of G protein-coupled receptors. Here, we demonstrate that, in ovarian cancer cells, ␤-arrestin is recruited to ETAR to form two trimeric complexes: one through the interaction with Src leading to epithelial growth factor receptor (EGFR) transactivation and ␤-catenin Tyr phosphorylation, and the second through the physical association with axin, contributing to release and inactivation of glycogen synthase kinase (GSK)-3␤ and ␤-catenin stabilization. The engagement of ␤-arrestin in these two signaling complexes concurs to activate ␤-catenin signaling pathways. We then demonstrate that silencing of both ␤-arrestin-1 and ␤-arrestin-2 inhibits ETAR-driven signaling, causing suppression of Src, mitogen-activated protein kinase (MAPK), AKT activation, as well as EGFR transactivation and a complete inhibition of ET-1-induced ␤-catenin/TCF transcriptional activity and cell invasion. ETAR blockade with the specific ETAR antagonist ZD4054 abrogates the engagement of ␤-arrestin in the interplay between ETAR and the ␤-catenin pathway in the invasive program. Finally, ETAR is expressed in 85% of human ovarian cancers and is preferentially co-expressed with ␤-arrestin-1 in the advanced tumors. In a xenograft model of ovarian metastasis, HEY cancer cells expressing ␤-arrestin-1 mutant metastasize at a reduced rate, highlighting the importance of this molecule in promoting metastases. ZD4054 treatment significantly inhibits metastases, suggesting that specific ETAR antagonists, by disabling multiple signaling activated by ETAR/␤-arrestin, may represent new therapeutic opportunities for ovarian cancer.beta-arrestin ͉ beta-catenin ͉ endothelin A receptor ͉ metastasis ͉ ovarian cancer

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mentioning

confidence: 91%

β-Arrestin links endothelin A receptor to β-catenin signaling to induce ovarian cancer cell invasion and metastasis

Rosanò¹,

Cianfrocca

Masi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

149

161

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“…4 Because inhibition of cell growth could also be due to the induction of apoptosis induced by ZD4054 or taxol, we therefore investigated whether ZD4054 could potentiate the effect of paclitaxel by inducing apoptosis compared with either single agent. ET A R activation by ET-1 triggers multiple signal transduction pathways that include MAPK and AKT pathways (8,15). In particular, we previously demonstrated that PI3K-dependent Akt pathway has a central role in ET A R-mediated protection against paclitaxeldependent apoptosis in ovarian cancer cells (16).…”

Section: Cell Proliferation Inhibition By Zd4054 and Paclitaxelmentioning

confidence: 99%

“…Two major receptor subtypes that mediate ET's biological effects belong to the G-protein coupled receptor family: the ET A receptor (ET A R) is considered as the major effector of the ET axis and binds ET-1 and ET-2 with high affinity and ET-3 with low affinity; whereas the ET B R binds all ET isopeptides with the equal affinity (7). Interestingly, in gene expression profiles of latestage ovarian cancer, ET A R was identified as a metastasisassociated gene that activates cell signaling involved in the control of cell migration, spread, and invasion (8,9). Levels of ET-1 are markedly elevated in the ascites of patients with epithelial ovarian cancer (10) and, together with the ET A R, are overexpressed and activated in 85% of ovarian tumors, correlating with advanced stages (7,11,12).…”

Section: Introductionmentioning

confidence: 99%

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Rosanò

Castro

Spinella

et al. 2007

Molecular Cancer Therapeutics

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The autocrine endothelin (ET)-1/endothelin A receptor (ET A R) pathway is an important regulator of several processes involved in ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET A R receptor as a potential target for improving ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of ZD4054, an orally active antagonist that specifically binds ET A R, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ET A Rpositive cell lines HEY, OVCA 433, SKOV-3, and A-2780, ZD4054 effectively inhibited the basal and ET-1 -induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. ZD4054 treatment also resulted in a reduction of ET A Rdriven angiogenesis and invasive mediators, such as vascular endothelial growth factor, cyclooxygenase-1/2, and matrix metalloproteinase (MMP). The combination of ZD4054 and paclitaxel led to the potentiation of all these effects, indicating that ZD4054, by blocking the ET A R-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to paclitaxel. In HEY ovarian cancer xenografts, ZD4054 significantly inhibited tumor growth to the same degree as paclitaxel. Furthermore, ZD4054-dependent tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of ZD4054 and paclitaxel produced additive antitumor effects, with 40% of mice remaining tumorfree, supporting a rationale for the clinical use of ZD4054 as monotherapy or in combination with cytotoxic drugs.

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“…Promising results have been reported in several cancers, including bladder, colon and breast cancers (Neibergs et al, 2002;van't Veer et al, 2002;Dyrskjot et al, 2003), of gene expression profiling as a new means for identifying diagnostic and prognostic targets. While this approach has been applied to ovarian cancer (Adib et al, 2004;Donninger et al, 2004;Hibbs et al, 2004;Lancaster et al, 2004;Lee et al, 2004;Lu et al, 2004;Santin et al, 2004;Warrenfeltz et al, 2004;Zhang et al, 2005), resulting in the identification of several hundred genes differentially expressed between NOSE (normal ovarian surface epithelia) and EOC, less than 10% of these genes were identified in common by at least two reports (Le Page et al, 2004). Although sample size, methods of evaluation and expression platforms vary and could account for differences in gene expression profiles, additional independent studies are required for cross-comparison to identify reliable gene markers that vary in expression.…”

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confidence: 99%

Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer

et al. 2006

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In order to elucidate the biological variance between normal ovarian surface epithelial (NOSE) and epithelial ovarian cancer (EOC) cells, and to build a molecular classifier to discover new markers distinguishing these cells, we analysed gene expression patterns of 65 primary cultures of these tissues by oligonucleotide microarray. Unsupervised clustering highlights three subgroups of tumours: low malignant potential tumours, invasive solid tumours and tumour cells derived from ascites. We selected 18 genes with expression profiles that enable the distinction of NOSE from these three groups of EOC with 92% accuracy. Validation using an independent published data set derived from tissues or primary cultures confirmed a high accuracy (87 -96%). The distinctive expression pattern of a subset of genes was validated by quantitative reverse transcription -PCR. An ovarian-specific tissue array representing tissues from NOSE and EOC samples of various subtypes and grades was used to further assess the protein expression patterns of two differentially expressed genes (Msln and BMP-2) by immunohistochemistry. This study highlights the relevance of using primary cultures of epithelial ovarian cells as a model system for gene profiling studies and demonstrates that the statistical analysis of gene expression profiling is a useful approach for selecting novel molecular tumour markers.

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Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways

Cited by 118 publications

References 72 publications

β-Arrestin links endothelin A receptor to β-catenin signaling to induce ovarian cancer cell invasion and metastasis

β-Arrestin links endothelin A receptor to β-catenin signaling to induce ovarian cancer cell invasion and metastasis

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer

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