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Clin Cancer Res. 2018 Dec 15;24(24):6308-6318. doi: 10.1158/1078-0432.CCR-17-3535. Epub 2018 Aug 7.

Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.

Author information

1
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison Wisconsin.
2
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison Wisconsin.
3
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison Wisconsin. plambert@wisc.edu.

Abstract

PURPOSE:

Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption, and high-risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. NOTCH1 is among the most frequently mutated genes in both HPV-positive and HPV-negative HNSCC. These mutations are predicted to inactivate the function of Notch. Other studies have argued the opposite-Notch signaling is increased in HNSCC.

EXPERIMENTAL DESIGN:

To assess the role of Notch signaling in HPV-positive and HPV-negative HNSCC, we utilized genetically engineered mouse (GEM) models for conventional keratinizing HNSCC, in which either HPV16 E6 and E7 oncoproteins or a gain-of-function mutant p53 are expressed, and in which we inactivated canonical Notch signaling via expression of a dominant negative form of MAML1 (DNMAML1), a required transcriptional coactivator of Notch signaling.

RESULTS:

Loss of canonical Notch signaling increased tumorigenesis in both contexts and also caused an increase in nuclear β-catenin, a marker for increased tumorigenic potential. When combined with loss of canonical Notch signaling, HPV oncogenes led to the highest frequency of cancers overall and the largest number of poorly differentiated (high-grade) cancers.

CONCLUSIONS:

These findings inform on the contribution of loss of canonical Notch signaling in head and neck carcinogenesis.

PMID:
30087145
PMCID:
PMC6295262
[Available on 2019-12-15]
DOI:
10.1158/1078-0432.CCR-17-3535

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