Abstract 1290: The ability of the transcription factor p63 to induce selected gene expression modules associated with mesenchymal to epithelial transition of prostate cells

Genome-wide gene expression analysis identified p63 as one of the most consistently under-expressed transcription factors in prostate cancer samples compared to matched benign prostate tissue. Two alternative p63 promoters generate two different N-terminal variants, TA or ΔN which contains and lacks the transactivating domain, respectively. Differential splicing generates multiple additional isoforms. The activity and interactions of the different isoforms remain unresolved. Isoform-specific real-time quantitative PCR assays revealed that ΔNp63α is the predominant isoform in epithelial prostate tissues, but other isoforms are detectable. Our group has established an experimental cell culture model based upon primary, immortalized prostate epithelial cells (EP156T cells), where p63 was shut down when EP156T cells underwent epithelial-to-mesenchymal transition (EMT) to become EPT1 cells. Subsequently, several additional mesenchymal like cell subtypes with additional malignant features, including anchorage independent growth in soft agar and ability to grow at much higher density in monolayers, were derived from EPT1 cells. All of these subtypes exhibited very low p63 expression. To examine the potential of p63 to induce mesenchymal to epithelial transition (MET) in this EMT model, we have stably re-expressed the ΔNp63α and TAp63α isoforms in different mesenchymal like cells of the model using retroviral/lentiviral vector transductions. Genome-wide gene expression analyses and phenotypic cellular assays revealed that the ΔNp63α isoform induced re-expression of multiple genes involved in cell adhesion. But this was not associated with complete MET induction. Cells re-expressing ΔNp63α obtained an intermediate morphology with both epithelial and mesenchymal traits, and with actin filaments organized in stress fibers. ΔNp63α re-expression significantly compromised migratory but not invasive ability of the cells. Based upon these findings we want to investigate whether p63 may compromise epithelial to mesenchymal plasticity in an animal model of tumorigenic cells and if there is differential effect on primary tumor growth compared to metastatic growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1290. doi:1538-7445.AM2012-1290