Authors:

Abstract

Background: Palbociclib resistance is a significant problem in breast carcinoma, and its underlying molecular mechanisms remain poorly understood. This study aims to elucidate the molecular mechanisms of palbociclib resistance and to identify the key genes and pathways mediating progesterone resistance in breast cancer (BC).

Methods: Gene dataset GSE117743 was downloaded from the Gene Expression Omnibus (GEO) database, which included 3 palbociclib-resistant and 3 palbociclib-sensitive BC cell lines. Then, we calculated the differentially expressed genes (DEGs) by using R software. Gene ontology and Enriched pathway analysis of genes we identified were analyzed by using the Database for Database of Annotation Visualization and Integrated Discovery (DAVID) and R software. The protein-protein interaction network was performed according to Metascape, String, and Cytoscape software.

Results: In total, 447 DEGs were selected, which consisted of 67 upregulated and 380 downregulated genes. According to gene ontology annotation, DEGs were associated with cytoplasm, signal transduction, and protein binding. The research of the Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated that genes enriched in certain tumor pathways, including IL-17 signaling pathways and Herpes simplex infection signaling pathways. Also, certain hub genes were highlighted after constructed and analyzed the protein-protein interaction network, including α-2A adrenergic receptor, cytochrome P450 subfamily IIR polypeptide, Cystathionine β-synthase, nucleotide-binding oligomerization domain-containing, erythropoietin-producing hepatocellular receptor A2 and adrenomedullin, which may be related with BC prognosis. A total of 4 of 6 hub genes had a significant relationship with the overall survival (P <0.05).

Conclusions: Using microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of progesterone resistance. We offered several possible mechanisms of progesterone resistance and identified therapeutic and prognostic targets of palbociclib resistance in BC.

Keywords: Progesterone resistance, Breast carcinoma, Bioinformatics, Progesterone receptor