E2F1-initiated transcription of PRSS22 promotes breast cancer metastasis by cleaving ANXA1 and activating the FPR2/ERK signaling pathways

Abstract Breast cancer (BC) is the most common malignant tumor in women worldwide. Metastasis is the main cause of BC-related death. The specific mechanism of BC metastasis remains obscure. Recently PRSS22 was discovered to be involved in tumor development. However, its detailed biological function and regulation mechanism in BC remain unclear. Here, we characterized that the PRSS22 expression level was upregulated in BC tissues compared with non-tumorous breast tissues. Dual Luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor E2F1 directly bounded to the PRSS22 promoter region and activated its transcription. Functionally, upregulation of PRSS22 promoted invasion and metastasis of BC cells in vitro and in vivo, whereas knockdown of PRSS22 elicited inhibition function. Mechanistically, the combination of PRSS22 and ANXA1 protein in BC cells was firstly screened by protein mass spectrometry analyses, and then confirmed by Co-immunoprecipitation (Co-IP) assays and Western blot assays. Co-overexpression of PRSS22 and ANXA1 could promote migration and invasion in BC cells. We further demonstrated that PRSS22 could promote the cleavage of ANXA1 and produce a N-terminal peptide, which could initiate the FPR2/ERK signaling axis to increase the aggressiveness of BC.