Impaired notch signaling promotes de novo squamous cell carcinoma formation.
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.
Proweller
Aaron
A
Cardiovascular Institute, and Department of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Tu
Lili
L
Lepore
John J
JJ
Cheng
Lan
L
Lu
Min Min
MM
Seykora
John
J
Millar
Sarah E
SE
Pear
Warren S
WS
Parmacek
Michael S
MS
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
C486455:Maml1 protein, mouse; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1