Multi-time scale transcriptomic analysis on the dynamic process of tamoxifen resistance development in breast cancer cell lines.

Abstract

Approximately 30% of breast cancer patients develop endocrine resistance after tamoxifen therapy. There still lacks a comprehensive understanding on the mechanism of tamoxifen resistance. This study aims to explore the dynamic process of ER + breast cancer resistance to tamoxifen through the time course transcriptomic analysis. The transcriptome profiles of human breast cancer cell line MCF-7 treated with tamoxifen at different time scales were collected from LINCS, SRA and GEO databases. Differentially expressed genes (DEGs) were identified in the short-term tamoxifen treatment and tamoxifen-resistant cell lines. The time course analysis was used to explore the dynamic development of tamoxifen resistance using the transcriptome profiles of tamoxifen-cultured MCF-7 for 1-12weeks. After the short-term treatment of MCF-7 with tamoxifen for 6h or 24h, the expression level of gene PRSS23 was significantly reduced. However, its expression recovered in the resistant cell lines. The time course analysis identified 9 clusters of the DEGs based on the temporal trend of their expression levels. Gene PRSS23 belongs to cluster 2 in which the expression levels were significantly down-regulated in the first 4weeks but gradually recovered afterwards. Functional enrichment analysis of the DEGs in cluster 2 showed that they are significantly enriched in DNA replication, mismatch repair and cell cycle pathways. Their specific role in the resistance development needs to be further explored. The protein-protein interaction network analysis indicates that gene PRSS23 participates in the drug resistance by regulating multiple tamoxifen drug targets. The acquired drug resistance in ER + breast cancer is a complex and dynamic biological process. PRSS23 plays an important role in the development of resistance and is a potential target for overcoming resistance.