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. What's new? Despite the loss of transcriptional activity, mutant p53 (mutp53) proteins display gain of function properties, such as the ability to contribute to tumor progression. To elucidate functional gains, the present study explored the effects of mutp53 expression in monotransgenic WAP-T mice and bitransgenic WAP-T x WAP-mutp53 mice. Mammary tumors from both models were phenotypically similar and possessed an epithelial-mesenchymal transition (EMT) gene signature associated with tumor cell plasticity. However, mammary tumors in bitransgenic mice showed enhanced metastatic potential. Additional findings from in vitro experiments indicate that the tumor microenvironment plays a key role in regulating tumor cell phenotype and invasiveness.