title: Mutant p53 promotes epithelial-mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP-T mice.
abstract: To study the postulated mutant p53 (mutp53) "gain of function" effects in mammary tumor development, progression and metastasis, we crossed SV40 transgenic WAP-T mice with mutant p53 transgenic WAP-mutp53 mice. Compared to tumors in monotransgenic WAP-T mice, tumors in bitransgenic WAP-T x WAP-mutp53 mice showed higher tumor grading, enhanced vascularization, and significantly increased metastasis. Bitransgenic tumors revealed a gene signature associated with the oncogenic epithelial-mesenchymal transition pathway (EMT gene signature). In cultures of WAP-T tumor-derived G-2 cancer cells, which are comprised of subpopulations displaying "mesenchymal" and "epithelial" phenotypes, this EMT gene signature was associated with the "mesenchymal" compartment. Furthermore, ectopic expression of mutp53 in G-2 cells sufficed to induce a strong EMT phenotype. In contrast to these in vitro effects, monotransgenic and bitransgenic tumors were phenotypically similar suggesting that in vivo the tumor cell phenotype might be under control of the tumor microenvironment. In support, orthotopic transplantation of G-2 cells as well as of G-2 cells expressing ectopic mutp53 into syngeneic mice resulted in tumors with a predominantly epithelial phenotype, closely similar to that of endogenous primary tumors. We conclude that induction of an EMT gene signature by mutp53 in bitransgenic tumors primarily promotes tumor cell plasticity, that is, the probability of tumor cells to undergo EMT processes under appropriate stimuli, thereby possibly increasing their potential to disseminate and metastasize.
authors.affiliation: Department for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany; Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Lenfert
authors.forename: Claudia
authors.initials: C
authors.lastname: Maenz
authors.forename: Christina
authors.initials: C
authors.lastname: Heinlein
authors.forename: Katharina
authors.initials: K
authors.lastname: Jannasch
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Genrich V
authors.initials: GV
authors.lastname: Tolstonog
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Deppert
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: EMT; WAP-T; breast cancer; metastasis; mutp53