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

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


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.

Publication types

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Viral
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Head and Neck Neoplasms / diagnosis
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / etiology*
  • Head and Neck Neoplasms / metabolism*
  • Human papillomavirus 16 / genetics
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / virology
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Severity of Illness Index
  • Signal Transduction* / drug effects
  • Transcription Factor HES-1 / genetics
  • Transcription Factor HES-1 / metabolism
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 16
  • MAML1 protein, human
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Transcription Factor HES-1
  • Transcription Factors
  • HES1 protein, human