LAUSR

Simple Summary Breast cancer is the most common cancer among women, and it can be classified into subtypes with distinct biology and prognosis. The aim of our bioinformatic study was to assess the potential role of the protein methyltransferase SETD7 in breast cancer by using freely available resources. We saw that SETD7 is differentially expressed across subtypes, which may determine how SETD7 modulates cancer cell biological processes in each subtype. This translates into different prognosis and therapeutic response in patients stratified according to SETD7 levels. SETD7 might provide valuable additional information for discriminating patients based on subtypes and improve therapeutic decisions. Abstract SETD7 is a lysine N-methyltransferase that targets many proteins important in breast cancer (BC). However, its role and clinical significance remain unclear. Here, we used online tools and multiple public datasets to explore the predictive potential of SETD7 expression (high or low quartile) considering BC subtype, grade, stage, and therapy. We also investigated overrepresented biological processes associated with its expression using TCGA-BRCA data. SETD7 expression was highest in the Her2 (ERBB2)-enriched molecular subtype and lowest in the basal-like subtype. For the basal-like subtype specifically, higher SETD7 was consistently correlated with worse recurrence-free survival (p < 0.009). High SETD7-expressing tumours further exhibited a higher rate of ERBB2 mutation (20% vs. 5%) along with a poorer response to anti-Her2 therapy. Overall, high SETD7-expressing tumours showed higher stromal and lower immune scores. This was specifically related to higher counts of cancer-associated fibroblasts and endothelial cells, but lower B and T cell signatures, especially in the luminal A subtype. Genes significantly associated with SETD7 expression were accordingly overrepresented in immune response processes, with distinct subtype characteristics. We conclude that the prognostic value of SETD7 depends on the BC subtype and that SETD7 may be further explored as a potential treatment-predictive marker for immune checkpoint inhibitors.