SETD7 Expression Is Associated with Breast Cancer Survival Outcomes for Specific Molecular Subtypes: A Systematic Analysis of Publicly Available Datasets

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.

Inhibiting SETD7 methyl‐transferase activity impairs differentiation, lipid metabolism and lactogenesis in mammary epithelial cells

“…We showed that SETD7 expression is gradually induced when mouse MECs decrease their proliferation rate and begin to differentiate. This is concordant with the observations in human BC, where the less differentiated molecular subtype (basal-like) has lower SETD7 levels than other molecular subtypes [60].…”

“…(R)‐PFI‐2 increased cell proliferation in both mammary epithelial cell lines studied, both in undifferentiated as well as functionally differentiated stages. Although we did not carry an in‐depth investigation of the pathways that may be involved in this effect, we recently reported that human BC samples with low SETD7 mRNA expression have an overrepresentation of proteins related with the cell cycle, checkpoint, and mitosis, including CCNA2 , CDK1 , PARP1 , TTK , and VEGFA [60]. Also, other authors have shown that SETD7 inhibits several proteins important for cell cycle progression (reviewed by [2]) that can become activated by (R)‐PFI‐2.…”