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Published on: February 8, 2013
Multi-time scale transcriptomic analysis on the dynamic process of tamoxifen resistance development in breast cancer
Qiuhong Zeng1, Xiaofang Lin1, Huadong Chen1
1Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China.
Background:
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.
Methods:
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 1-12 weeks.
Results:
After the short-term treatment of MCF-7 with tamoxifen for 6 h or 24 h, 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 4 weeks 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.
Conclusions:
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.
Insights
Tamoxifen resistance in ER+ breast cancer is complex. Gene PRSS23 is downregulated early but recovers, playing a key role in tamoxifen resistance development and offering a potential therapeutic target.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Endocrine resistance affects 30% of breast cancer patients post-tamoxifen therapy.
- Mechanisms of tamoxifen resistance require further elucidation.
- Estrogen receptor-positive (ER+) breast cancer is a significant clinical challenge.
Purpose of the Study:
- To investigate the dynamic process of tamoxifen resistance in ER+ breast cancer.
- To identify key genes and pathways involved in tamoxifen resistance development.
- To explore the role of gene PRSS23 in acquired tamoxifen resistance.
Main Methods:
- Transcriptomic analysis of MCF-7 cell lines treated with tamoxifen over time.
- Identification of differentially expressed genes (DEGs) using time-course analysis.
- Functional enrichment and protein-protein interaction network analysis.
Main Results:
- Gene PRSS23 expression was significantly reduced after short-term tamoxifen treatment but recovered in resistant cells.
- Time-course analysis revealed 9 DEG clusters, with PRSS23 in a cluster showing initial downregulation and subsequent recovery.
- DEGs in cluster 2 are enriched in DNA replication, mismatch repair, and cell cycle pathways, suggesting their role in resistance.
Conclusions:
- Acquired tamoxifen resistance in ER+ breast cancer is a dynamic and intricate biological process.
- Gene PRSS23 is implicated in tamoxifen resistance development and may serve as a therapeutic target.
- Further research is needed to fully understand the specific role of PRSS23 and associated pathways in resistance.
