Serine protease Prss14 as a new prognosis marker and therapeutic target on the triple negative breast cancer

초록

We previously showed that Prss14/ST14, a type II transmembrane serine protease, is critically involved in angiogenesis, EMT, transendothelial migration of cancer cell lines and activated macrophages, and metastasis in mouse breast cancer models. We verified the significance of Prss14/ST14 in human breast cancer by utilizing publically accessible databases including TCGA, GEO, NCI-60, and CCLE. Survival of breast cancer patients with high Prss14/ST14 expression is significantly poor in estrogen receptor (ER) negative and triple negative (TN) populations regardless of the ratios of Prss14/ST14 to its inhibitors, SPINT1 or SPINT2. Thus, Prss14/ST14 alone can be a therapeutic target for TN breast cancer where HER2 is not applicable. Prss14/ST14 is located in the same cluster with CDH3, and closer to post-EMT markers, CDH2, VIM, and FN1 than to the pre-EMT marker, CDH1, in a clustering of 1085 selected EMT signature genes. Coexpression analyses of known ST14/Prss14 substrates and transcription factors revealed context dependent action, indicating personalized precision medicine is required for using Prss14/ST14 structure specific immunological agents. In cell lines, paradoxically, Prss14/ST14 expression is higher in the ER positive group and located closer to CDH1 in clustering. This apparent contradiction is not likely due to Prss14/ST14 expression in a cancer microenvironment, nor due to negative regulation by ER. Therefore, we suggest that careful conclusions should be drawn not exclusively from the cell line studies for target development.