title: Salivary gland tumors in transgenic mice with targeted PLAG1 proto-oncogene overexpression.
abstract: Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well.
authors.affiliation: Laboratory for Molecular Oncology, Department of Human Genetics, K.U. Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Declercq
authors.forename: Frederik
authors.initials: F
authors.lastname: Van Dyck
authors.forename: Caroline V
authors.initials: CV
authors.lastname: Braem
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Van Valckenborgh
authors.forename: Marianne
authors.initials: M
authors.lastname: Voz
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Van Damme
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.forename: Wim J M
authors.initials: WJ
authors.lastname: Van de Ven
mesh_terms: D008949:Adenoma, Pleomorphic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C104382:PLAG1 protein, human; D000090063:Proto-Oncogene Mas