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Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice
Author(s) -
Lenfert Eva,
Maenz Claudia,
Heinlein Christina,
Jannasch Katharina,
Schumacher Udo,
Pantel Klaus,
Tolstonog Genrich V.,
Deppert Wolfgang,
Wegwitz Florian
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29186
Subject(s) - biology , cancer research , metastasis , epithelial–mesenchymal transition , ectopic expression , mammary tumor , genetically modified mouse , mesenchymal stem cell , tumor progression , transgene , cell culture , pathology , microbiology and biotechnology , cancer , gene , medicine , breast cancer , genetics
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.