Low CDKN1B expression accompanied by reduced tumor-infiltrating lymphocytes is correlated with an adverse prognosis in breast cancer: machine learning analysis and drug discovery

Abstract

Abstract The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene encodes the p27Kip1 protein, which plays an important role in cell cycle regulation and cell proliferation, and its role in breast cancer prognosis is controversial. The aim of this study was to analyze the clinicopathological parameters, molecular interactions, and anticancer immune responses in patients with CDKN1B expression. We investigated the clinicopathologic parameters, survival rates, proportions of immune cells, gene sets and prognostic models according to CDKN1B expression in 3,149 breast cancer patients. We performed gene set enrichment analysis (GSEA), in silico cytometry, pathway network analyses, in vitro drug screening and gradient boosting machine (GBM) learning. High CDKN1B expression levels in breast cancer correlated with high lymphocyte infiltration signature scores and increased CD8 + T cells, which were associated with a better prognosis. CDKN1B expression was associated with gene sets for upregulation of T-cell receptor signaling pathways and downregulation of CD8 + T cells. Pathway network analysis showed that CDKN1B was linked directly to positive regulation of the protein catabolic process pathway and indirectly to the T-cell receptor signaling pathway. We found that BMS-345541 was an effective drug that targeted CDKN1B and effectively supressed the growth of breast cancer cells with low CDKN1B expression in drug screening. The GBM model that included CDKN1B expression exhibited improved performance in predicting survival. CDKN1B expression may play an important role in the progression of breast cancer, and targeting CDKN1B may be a potential strategy for the treatment of breast cancer.