title: Loss of Rad51c accelerates tumourigenesis in sebaceous glands of Trp53-mutant mice.
abstract: Germline mutations in RAD51C predispose to breast and ovarian cancers. However, the mechanism of RAD51C-mediated carcinogenesis is poorly understood. We previously reported a first-generation Rad51c-knock-out mouse model, in which a spontaneous loss of both Rad51c and Trp53 together resulted in a high incidence of sebaceous carcinomas, particularly in preputial glands. Here we describe a second-generation mouse model, in which Rad51c is deleted, alone or together with Trp53, in sebaceous glands, using Cre-mediated recombination. We demonstrate that deletion of Rad51c alone is not sufficient to drive tumourigenesis and may only cause keratinization of preputial sebocytes. However, deletion of Rad51c together with Trp53 leads to tumour development at around 6 months of age, compared to 11 months for single Trp53-mutant mice. Preputial glands of double-mutant mice are also characterized by increased levels of cell proliferation and DNA damage and form multiple hyperplasias, detectable as early as 2 months of age. Our results reveal a critical synergy between Rad51c and Trp53 in tumour progression and provide a predictable in vivo model system for studying mechanisms of Rad51c-mediated carcinogenesis.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Tumiati
authors.forename: Annabrita
authors.initials: A
authors.lastname: Hemmes
authors.forename: Sanna
authors.initials: S
authors.lastname: Uusivirta
authors.forename: Sonja
authors.initials: S
authors.lastname: Koopal
authors.forename: Matti
authors.initials: M
authors.lastname: Kankainen
authors.forename: Eero
authors.initials: E
authors.lastname: Lehtonen
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Kuznetsov
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D051135:Rad51 Recombinase / Q000235:genetics*; D012627:Sebaceous Glands / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C519208:RAD51C protein, mouse; D016159:Tumor Suppressor Protein p53; D051135:Rad51 Recombinase
keywords: Msh2; Rad51c; Trp53; mouse model; preputial gland; sebaceous