SET-binding protein 1 (SETBP1) suppresses cell proliferation in estrogen receptor-positive breast cancer

Background: The single-nucleotide polymorphism rs6507583 at the promoter of SET-binding protein 1 (SETBP1) was implicated in estrogen receptor (ER)-positive breast carcinogenesis. Here, we evaluated the clinical and biological relevance of SETBP1 expression in ER-positive breast cancer (BC). Methods: The associations between SETBP1 expression and clinical outcomes in BC patients were analyzed in independent cohorts. The localizations of SETBP1 expression in BC tissues were observed by immunohistochemical staining. Pathway analyses were conducted using TCGA dataset. In vitro proliferation assay, protein phosphatase 2A (PP2A) activity assay, and gene expression analysis were performed in SETBP1-knockdown ER-positive BC cells. We investigated the factors influencing SETBP1 mRNA expression using TCGA dataset. rs6507583 presence and SETBP1 mRNA expression in 11 mammary cell lines and 56 BC tissue samples were examined by target sequencing and RT-qPCR, respectively. Results: SETBP1 was downregulated in BC cells compared with normal ductal epithelial cells. Low SETBP1 mRNA expression was an independent prognostic factor for poor recurrence-free survival. Pathway analyses revealed an inverse relationship between decreased SETBP1 expression and the expression of E2F, MYC, and G2M checkpoint target genes in BC tissues. SETBP1 knockdown promoted proliferation, inhibition of PP2A activity, and phosphorylation of MAPK in ER-positive BC. Low SETBP1 expression was influenced by high SETBP1 promoter methylation and DNA copy number SETBP1 deletion. SETBP1 expression with rs6507583 was lower than without rs6507583 in BC. Conclusions: We demonstrated that low SETBP1 expression could be a poor prognostic biomarker that promotes ER-positive BC proliferation, possibly via phosphorylation of MAPK.