Notch3 pathway alterations in ovarian cancer

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • 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