title: Increased incidence of squamous cell carcinomas in Mastomys natalensis papillomavirus E6 transgenic mice during two-stage skin carcinogenesis.
abstract: Papillomaviruses cause certain forms of human cancers, most notably carcinomas of the uterine cervix. In contrast to the well-established involvement of papillomavirus infection in the etiology of cervical carcinomas and in carcinomas of a rare hereditary condition, epidermodysplasia verruciformis, a causative role for cutaneous human papillomavirus types in the development of nonmelanoma skin cancer has not been proven. In order to better understand the functions of individual genes of cutaneous papillomavirus types, we generated transgenic mice carrying oncogene E6 of the Mastomys natalensis papillomavirus (MnPV), which causes keratoacanthomas of the skin in its natural host. In the present study, we demonstrate that under conditions of experimental two-stage skin carcinogenesis, fast-paced squamous cell carcinomas develop in nearly 100% of MnPV E6 transgenic mice in comparison to 10% in their nontransgenic littermates (log rank test; P < 0.0001). Therefore, we conclude that the MnPV E6 transgene favors the malignant progression of chemically induced tumors. Whereas an activating H-ras mutation is a consistent feature in benign and malignant tumors in wild-type mice, the majority of papillomas and keratoacanthomas and all squamous cell carcinomas obtained in MnPV E6 transgenic mice contain nonmutated ras alleles. These results indicate that the development of squamous cell carcinomas in MnPV E6 transgenic mice does not depend on an activated H-ras oncogene.
authors.affiliation: Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany. i.helfrich@dkfz.de
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Rainer
authors.initials: R
authors.lastname: Schmidt
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: David
authors.initials: D
authors.lastname: Trick
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Harald
authors.initials: H
authors.lastname: Zur Hausen
authors.forename: Frank
authors.initials: F
authors.lastname: Rösl
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D011905:Genes, ras / Q000235:genetics; D015994:Incidence; D051379:Mice; D008822:Mice, Transgenic; D009115:Muridae / Q000821:virology*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000503:physiopathology*; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004268:DNA-Binding Proteins; C075298:E6 protein, Old World harvest mouse papillomavirus; D009687:Nuclear Proteins; D014764:Viral Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene