Notch3 Pathway Alterations in Ovarian Cancer

Hu, Wei; Liu, Tao; Ivan, Cristina; Sun, Yunjie; Huang, Jie; Mangala, Lingegowda S.; Miyake, Takahito; Dalton, Heather J.; Pradeep, Sunila; Rupaimoole, Rajesha; Previs, Rebecca A.; Han, Hee Dong; Bottsford-Miller, Justin; Zand, Behrouz; Kang, Yu; Pecot, Chad V.; Nick, Alpa M.; Wu, Sherry Y.; Lee, Ju Seog; Sehgal, Vasudha; Ram, Prahlad T.; Liu, Jinsong; Tucker, Susan L.; López-Berestein, Gabriel; Baggerly, Keith A.; Coleman, Robert L.; Sood, Anil K.

doi:10.1158/0008-5472.can-13-2066

Cited by 59 publications

(51 citation statements)

References 20 publications

(22 reference statements)

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“…Notch 3 protein overexpression was associated with ovarian cancer metastasis, chemoresistance and poor overall survival in ovarian serous cancer patients [47]. Inhibition of Notch3 inhibited ovarian cancer growth and induced apoptosis [48]. In comparison with gamma-secretase inhibitor (GSI) in the treatment of paclitaxel in paclitaxel-resistant cancer cells, Notch3 siRNA specific inhibition showed more efficacy [49].…”

Section: Discussionmentioning

confidence: 99%

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

et al. 2017

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Aberrant activation of Notch signaling pathway has been correlated with high grade ovarian carcinoma and carcinogenesis. However, the predictive and prognostic values of Notch signaling pathway in ovarian cancer patients remains unclear. We utilize “The Kaplan-Meier plotter” (KM plotter) background database to access the prognostic values including overall survival (OS), progression-free survival (PFS), as well as post-progression survival (PPS) of four Notch receptor mRNA expression in ovarian cancer patients. Notch1 mRNA high expression was not correlated with OS, PFS and PPS for all ovarian cancer patients, but significantly correlated with poor PFS in TP53 wild type and favorite PFS in TP53 mutation type ovarian cancer patients. Notch2 mRNA high expression was significantly correlated with poor PFS for all ovarian cancer patients, especially in grade II patients. Notch3 mRNA high expression was significantly correlated with favorite PFS for all ovarian cancer patients. Notch4 mRNA high expression was significantly correlated with favorite OS, but not PFS and PPS for all ovarian cancer patients. The results strongly support that there are distinct prognostic values of four Notch receptor mRNA expression in ovarian cancer patients.

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Section: Discussionmentioning

confidence: 99%

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

et al. 2017

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“…Cultured cell lysates were prepared using a modified RIPA buffer including both a protease inhibitor and phosphatase inhibitor, and the protein concentrations were determined using a BCA Protein Assay Reagent kit (Pierce Biotechnology), as previously described (22, 23). The lysates were loaded and separated on 8% and 12% sodium dodecyl sulfate-polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer

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Previs

et al. 2015

Molecular Cancer Therapeutics

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PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN mutated and PTEN-wild type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared to Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared to the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to treatment FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development.

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“…Notch3 amplification and rearrangement have been repeatedly observed in ovarian cancer [143]. WWP2 was shown to interact with and monoubiquitinate the membraneanchored fragment of Notch3, leading to its degradation, possibly via the endosomal/lysosomal pathway.…”

Section: Wwpsmentioning

confidence: 97%