BackgroundBreast cancer ranks among the most prevalent tumor types worldwide. Copy number amplification of chromosome 8q24 is frequently detected in breast cancer. ZNF623 is a relatively unexplored gene mapped to 8q24. Here, we explore the expression profile, prognostic significance, and biological action of ZNF623 in breast carcinogenesis. MethodsTo evaluate the mRNA expression pattern and prognostic relevance of ZNF623 across different cancer types, we conducted bioinformatic analyses. The expression of the gene was suppressed using ZNF623 shRNAs/siRNAs and augmented through transfection with plasmids containing ZNF623 cDNA. Cell viability assay, clonogenic assay, and transwell migration assay were utilized to assess the proliferation, viability, and invasion capacity of breast cancer cell lines. Luciferase reporter assay served as a pivotal tool to ascertain the transcriptional activity of ZNF623. IP-MS and co-IP were employed to validate that ZNF623 interacted with CtBP1. ChIP analysis and ChIP-qPCR were conducted to assess the genes targeted by ZNF623/CtBP1 complex. Flow cytometry was conducted to evaluate the phosphorylation status of p65. ResultsZNF623 expression was notably elevated in breast cancer (BC). Prognostic analysis indicated higher expression of ZNF623 indicated worse survival. Functional experiments discovered that the upregulation of ZNF623 significantly enhanced both the proliferative and migratory capacities of breast cancer cells. Luciferase reporter assay indicated that ZNF623 was a transcription repressor. Immunoprecipitation coupled mass spectrometry analysis revealed a physical association between ZNF623 and CtBP1 in the interaction group. The conjoint analysis of ChIP-seq and TCGA DEG analysis revealed that the ZNF623/CtBP1 complex repressed a series of genes, such as negative regulation of the NF-kappaB signaling pathway. Flow cytometry analysis discovered that knockdown of ZNF623 decreased the phosphorylation level of p65, indicating that ZNF623 could regulate the activity of the NF-κB pathway. ConclusionZNF623 predicts poor prognosis of BC and enhances breast cancer growth and metastasis. By recruiting CtBP1, ZNF623 could suppress NF-κB inhibitors, including COMMD1, NFKBIL1, PYCARD, and BRMS1, expression from the transcription level.