Mutant p53 and ELK1 co‐drive FRA‐1 expression to induce metastasis in breast cancer

Tumor‐associated p53 mutations induce activities different from wild‐type p53, thus causing loss of the protein's tumor inhibition function. The cells carrying p53 mutations have more aggressive characteristics related to invasion, metastasis, proliferation, and cell survival. By comparing the gene expression profiles of mutant p53 (mutp53) and mutp53 silenced cohorts, we found that FOS‐related antigen‐1 (FRA‐1), which is encoded by FOSL1, is a potential effector of mutp53‐mediated metastasis. We demonstrate that the expression of FRA‐1, a gatekeeper of mesenchymal–epithelial transition, is elevated in the presence of p53 mutations. Mechanistically, mutant p53 cooperates with the transcription factor ELK1 in binding and activating the promoter of FOSL1, thus fostering lung metastasis. This study reveals new insights into how mutant p53 contributes to metastasis in breast cancer. In this study, we show that mutant p53 promotes FOS‐related antigen‐1 (FRA‐1) expression to impact epithelia‐to‐mesenchymal transition (EMT) in breast cancer. Mutant p53 is recruited to the promoter of FOSL1 (which encodes FRA‐1), where it binds ELK1 to assemble a transcription factor complex which subsequently augments FRA‐1 transcription. Increased FRA‐1 expression mediates the prometastatic gain‐of‐function of mutp53 through the EMT process.