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Jun 15, 2014;74 (12): 3282-93.

Notch3 pathway alterations in ovarian cancer.

Wei Hu, Tao Liu, Cristina Ivan, Yunjie Sun, Jie Huang, Lingegowda S Mangala, Takahito Miyake, Heather J Dalton, Sunila Pradeep, Rajesh Rupaimoole, Rebecca A Previs, Hee Dong Han, Justin Bottsford-Miller, Behrouz Zand, Yu Kang, Chad V Pecot, Alpa M Nick, Sherry Y Wu, Ju-Seog Lee, Vasudha Sehgal, Prahlad Ram, Jinsong Liu, Susan L Tucker, Gabriel Lopez-Berestein, Keith A Baggerly, Robert L Coleman, Anil K Sood
Author Information
  1. Wei Hu: 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.
  2. Tao Liu: 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.
  3. Cristina Ivan: 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.
  4. Yunjie Sun: 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.
  5. Jie Huang: 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.
  6. Lingegowda S Mangala: 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.
  7. Takahito Miyake: 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.
  8. Heather J Dalton: 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.
  9. Sunila Pradeep: 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.
  10. Rajesh Rupaimoole: 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.
  11. Rebecca A Previs: 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.
  12. Hee Dong Han: 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.
  13. Justin Bottsford-Miller: 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.
  14. Behrouz Zand: 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.
  15. Yu Kang: 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.
  16. Chad V Pecot: 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.
  17. Alpa M Nick: 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.
  18. Sherry Y Wu: 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.
  19. Ju-Seog Lee: 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.
  20. Vasudha Sehgal: 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.
  21. Prahlad Ram: 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.
  22. Jinsong Liu: 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.
  23. Susan L Tucker: 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.
  24. Gabriel Lopez-Berestein: 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.
  25. Keith A Baggerly: 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.
  26. Robert L Coleman: 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.
  27. Anil K Sood: 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.
PMID: 24743243 DOI: 10.1158/0008-5472.CAN-13-2066

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.

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Grants

  1. P30 CA016672/NCI NIH HHS
  2. R01 CA109298/NCI NIH HHS
  3. P50 CA098258/NCI NIH HHS
  4. U54 CA151668/NCI NIH HHS
  5. U54CA151668/NCI NIH HHS
  6. P50 CA083639/NCI NIH HHS
  7. R01 CA128797/NCI NIH HHS
  8. T32 CA101642/NCI NIH HHS
  9. CA109298/NCI NIH HHS
  10. CA128797/NCI NIH HHS
  11. UH2 TR000943/NCATS NIH HHS
  12. R01 CA177909/NCI NIH HHS

MeSH Term

Animals
Antineoplastic Agents, Phytogenic
Apoptosis
Calcium-Binding Proteins
Cell Line, Tumor
Dynamins
Endocytosis
Female
Gene Knockdown Techniques
Humans
Intercellular Signaling Peptides and Proteins
Jagged-1 Protein
Kaplan-Meier Estimate
Membrane Proteins
Mice
Mice, Nude
Neoplasms, Cystic, Mucinous, and Serous
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms
Paclitaxel
RNA, Small Interfering
Receptor, Notch3
Receptors, Notch
Serrate-Jagged Proteins
Transcriptome
Tumor Burden
Xenograft Model Antitumor Assays

Chemicals

Antineoplastic Agents, Phytogenic
Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
NOTCH3 protein, human
RNA, Small Interfering
Receptor, Notch3
Receptors, Notch
Serrate-Jagged Proteins
Dynamins
Paclitaxel
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0Notch3ovarianpathwayalterationscancerNotchgrowthclinicalmechanismsfoundpoorsignalingtherapyidentifyplaysimportantrolehigh-gradeserousHGS-OvCacancersbiologicwellunderstoodprevalentsignificantlyrelatedoutcomepatientsParticularlyincludingamplificationupregulationhighlyassociatedpatientsurvivalTargetinginhibitedinducedapoptosisImportantlydynamin-mediatedendocytosisrequiredselectivelyactivatingJagged-1-mediatedCleavedexpressioncriticaldeterminantresponseNotch-targetedCollectivelydatapreviouslyunknownunderlyingnewbiomarker-drivenapproaches

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