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Cancer Res. 2014 Jun 15;74(12):3282-93. doi: 10.1158/0008-5472.CAN-13-2066. Epub 2014 Apr 17.

Notch3 pathway alterations in ovarian cancer.

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1
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
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.
3
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.
4
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.

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.

PMID:
24743243
PMCID:
PMC4058356
DOI:
10.1158/0008-5472.CAN-13-2066
[Indexed for MEDLINE]
Free PMC Article

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