The main objective of this study is to elucidate the role of Notch3 signaling in the pathogenesis of ovarian cancer, one of the most lethal neoplastic diseases in women. It has been well-established that the Notch signaling is required during diverse developmental and physiological processes and aberration of the signaling pathway participates in cancer development. Based on our recent findings showing Notch3 gene amplification in ovarian cancers and its role in maintaining cell survival, we hypothesize that i) activation of Notch3 signaling pathway initiates tumor formation and/or propel tumor progression;ii) Pbx1, a Notch3-regulated gene, is responsible for the tumor-promoting phenotypes of Notch3 through its interaction with Hox proteins;iii) targeting the Notch3 signaling pathway has anti-tumor potential in cancer cells with active Notch signaling. To test the above hypotheses, we propose the following specific aims:
Aim 1 : Analyze the roles of Notch3 pathway activation in the development of ovarian carcinoma.
Aim 2 : Investigate the mechanism by which Pbx1 mediates tumor-promoting effects of Notch3 signaling.
Aim 3 : Assess anti- tumor potential of pharmacological targeting of the Notch3 pathway. The results from this study will address several critical questions centering the roles of Notch3 in cancer biology and should have implication for future development of Notch3-based target therapy.

Public Health Relevance

The purpose of this study is to determine the molecular mechanism by which Notch3 pathway activation contributes to the development of ovarian cancer. Furthermore, we will delineate the role of a Notch3 target gene in modulating oncogenic phenotypes in ovarian cancer. We will test tumor suppressive effect using newly developed small molecules to block Notch3-Pbx1 pathway. The results from this study will further our understanding the molecular mechanisms in the tumorigenesis of ovarian cancer and will provide foundation for Notch3-based cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Sathyamoorthy, Neeraja
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Johns Hopkins University
Obstetrics & Gynecology
Schools of Medicine
United States
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Yu, Yu; Suryo Rahmanto, Yohan; Lee, Meng-Horng et al. (2018) Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. Oncogene 37:3778-3789
Shi, Xu; Wang, Xiao; Wang, Tian-Li et al. (2018) SparseIso: a novel Bayesian approach to identify alternatively spliced isoforms from RNA-seq data. Bioinformatics 34:56-63
Jung, Jin-Gyoung; Shih, Ie-Ming; Park, Joon Tae et al. (2016) Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1. Cancer Res 76:6351-6361
Chen, Xi; Jung, Jin-Gyoung; Shajahan-Haq, Ayesha N et al. (2016) ChIP-BIT: Bayesian inference of target genes using a novel joint probabilistic model of ChIP-seq profiles. Nucleic Acids Res 44:e65
Suryo Rahmanto, Yohan; Jung, Jin-Gyoung; Wu, Ren-Chin et al. (2016) Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells. J Biol Chem 291:9690-9
Chui, M Herman; Wang, Yihong; Wu, Ren-Chin et al. (2015) Loss of ALDH1A1 expression is an early event in the pathogenesis of ovarian high-grade serous carcinoma. Mod Pathol 28:437-45
Yu, Yu; Gaillard, Stephanie; Phillip, Jude M et al. (2015) Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules. Cancer Cell 28:82-96
Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin et al. (2015) Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models. Clin Cancer Res 21:4652-62
Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J et al. (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24
Guan, Bin; Rahmanto, Yohan Suryo; Wu, Ren-Chin et al. (2014) Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis. J Natl Cancer Inst 106:

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