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Impaired notch signaling promotes de novo squamous cell carcinoma formation.
- Source :
-
Cancer research [Cancer Res] 2006 Aug 01; Vol. 66 (15), pp. 7438-44. - Publication Year :
- 2006
-
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 beta-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.
- Subjects :
- Animals
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell pathology
Cyclin D1 biosynthesis
Cyclin D1 metabolism
Humans
Mice
Mice, Transgenic
Nuclear Proteins biosynthesis
Nuclear Proteins genetics
Receptors, Notch metabolism
Signal Transduction physiology
Skin metabolism
Skin Neoplasms genetics
Skin Neoplasms pathology
Transcription Factors biosynthesis
Transcription Factors genetics
Up-Regulation
beta Catenin metabolism
Carcinoma, Squamous Cell metabolism
Receptors, Notch antagonists & inhibitors
Skin Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16885339
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-06-0793