title: Notch3 pathway alterations in ovarian cancer.
abstract: The Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biologic mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited ovarian cancer growth and induced apoptosis. Importantly, we found that dynamin-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Takahito
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sehgal
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Prahlad
authors.initials: P
authors.lastname: Ram
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Tucker
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Systems Biology, Pathology, Experimental Therapeutics, Bioinformatics and Computational Biology, Cancer Biology, Thoracic/Head and Neck Medical Oncology, and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas asood@mdanderson.org.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C499374:NOTCH3 protein, human; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D034281:Dynamins; D017239:Paclitaxel
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