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Updated: Sep 8, 2026

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
NOTCH3 Internal Tandem Duplication Defines a Novel Oncogenic Activation Mechanism of NOTCH Signaling
Hongyi Gao1, Si Chen2,3, Ying Wu1
1Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, China.
Abstract:
NOTCH signaling is activated in tumors through multiple mechanisms, including mutations, gene rearrangements, and gene amplification. We report a novel activation mechanism, an internal tandem duplication (ITD) near the NOTCH3 negative regulatory region (NRR), found in a myogenic mesenchymal neoplasm. This 17-amino acid residue duplication disrupts the tightly autoinhibited structure surrounding the S2 cleavage site, resulting in ligand-independent S2 cleavage and constitutive pathway activation, as demonstrated by increased expression of the NOTCH3 target gene HES1. Cells expressing NOTCH3-ITD showed increased nuclear localization of the receptor and exhibited malignant phenotypes, including enhanced proliferation and migration. Together, these findings support the oncogenic role of NOTCH3-ITD.
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