Impaired Notch Signaling Promotes De novo Squamous Cell Carcinoma Formation

Loading...
Thumbnail Image
Penn collection
Institute for Medicine and Engineering Papers
Degree type
Discipline
Subject
Funder
Grant number
License
Copyright date
Distributor
Related resources
Contributor
Abstract

Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor–mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)–dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear ß-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies.

Advisor
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Publication date
2006-08-01
Journal title
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Reprinted from Cancer Research, Volume 66, Issue 15, August 1 2006, pages 7438-44. Publisher URL: http://cancerres.aacrjournals.org/cgi/reprint/66/15/7438.pdf
Recommended citation
Collection