Abnormal Expression of Cell Cycle-Related Genes Promoting Estrogen Receptor-Positive Breast Cancer Resistant to Palbociclib

Background: Palbociclib as a selective CDK4/6 inhibitor, has already been applied to the treatment of estrogen receptor (ER)-positive breast cancer. However, the phenomenon of palbociclib resistance is not uncommon, and the underlying molecular mechanisms have not yet been well illustrated. Objective: The primary purpose of this study was to identify the abnormally expressed genes and their critical functions in palbociclib-resistant breast cancer, thus exploring the potential molecular mechanisms of palbociclib resistance. Methods: The gene expression dataset GSE93204 was used, which contains gene expression data from 118 breast cancer patient samples from clinical trial NCT01723774, including baseline tumor biopsy, biopsy after anastrozole treatment, biopsy after the combination of anastrozole and palbociclib treatment, and surgery. The palbociclib-resistant group and palbociclib-sensitive group were identified during the treatment process. Differentially expressed genes (DEGs) between palbociclib-resistant and palbociclib-sensitive breast cancer tissues were obtained. Significant DEGs, the functions of key genes, and the dysregulation of signaling pathways were identified and explored via bioinformatic analysis. Results: A total of 642 DEGs were selected between palbociclib-resistant and palbociclib–sensitive breast cancer tissues. Gene ontology (GO) analysis showed that DEGs were mainly associated with the regulation of cell proliferation, regulation of immune response, G1/S transition of mitotic cell cycle, protein kinase binding, and protein homodimerization activity. Kyoto Encyclopedia of Gene and Genome (KEGG) analysis demonstrated that DEGs were mainly enriched in the cell cycle, antigen processing and presentation. Protein-protein interaction (PPI) network and modular analysis selected three significant clusters containing 56 genes in total, and there were 25 common genes between PPI modular analysis and KEGG pathway results, 12 of these 25 genes were found to be significantly correlated with relapse-free survival (RFS) and 10 of these 25 genes significantly correlated with overall survival (OS). Most of them were cell cycle-related genes (CCND1, CDC7, CDC20, CDK1, CHEK1, E2F1, MCM2, MCM5, ORC6, PKMYT1, etc.), and could not be effectively suppressed by palbociclib in palbociclib-resistant tumor tissues. Conclusions: The present study used integrated bioinformatic methods to identify crucial cell cycle-related genes associated with palbociclib-resistance in ER-positive breast cancer. These findings may comprise potential prognostic biomarkers and therapeutic targets. Funding Statement: This paper was sponsored by the grant from the National Natural Science Foundation of China, No. 81872160, and the Ph.D. Innovation Fund of Cancer Hospital, Chinese Academy of Medical Sciences, No. C2019-1051-09. Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.