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Identification and characterization of biomarkers and their functions for Lapatinib-resistant breast cancer
Liang Zhang1, Yi Huang2, Wenlei Zhuo3
1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, China.
Abstract:
Lapatinib, a novel oral dual tyrosine kinase inhibitor blocking HER1 and HER2 pathways, has presented beneficial effects on breast cancer with positive HER2. However, its efficacy is largely limited by the occurrence of acquired drug resistance. In this study, we aimed to explore the underlying molecular mechanisms of Lapatinib resistance using bioinformatics strategies. The gene expression profile of SKBR3-R (acquired Lapatinib-resistant) and SKBR3 (Lapatinib-sensitive) cell line was downloaded from gene expression omnibus database. Then, the differentially expressed genes (DEGs) were selected using dChip software. Furthermore, gene ontology (GO) and pathway enrichment analyses were carried out by using DAVID database. Finally, the protein-protein interaction network was constructed, and the hub genes in the network were analyzed by using STRING database. A total of 300 DEGs, such as HSPA5, MAP1LC3A and RASSF2, were screened out. GO functional enrichment analysis showed that the genes were associated with cell membrane component-related, stimulus-related and binding-related items. KEGG pathway analysis indicated that three dysfunctional pathways, including PPAR signaling pathway, cytokine-cytokine receptor interaction and pathways in cancer, were enriched. Protein-protein interaction network construction revealed that some hub genes, such as PPARG, TGFBI, TGFBR2, TIMP1, CTGF, UBA52 and JUN, might have an association with Lapatinib resistance. The present study offered new insights into the molecular mechanisms of Lapatinib resistance and identified a series of important hub genes that have the potential to be the targets for treatment of Lapatinib-resistant breast cancer.
Insights
This study uncovers key molecular mechanisms driving Lapatinib resistance in breast cancer. It identifies crucial hub genes, offering potential new targets for treating resistant HER2-positive breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Lapatinib is an effective tyrosine kinase inhibitor for HER2-positive breast cancer.
- Acquired drug resistance significantly limits Lapatinib's long-term efficacy.
- Understanding resistance mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the molecular mechanisms underlying acquired Lapatinib resistance in breast cancer.
- To identify differentially expressed genes (DEGs) and key hub genes associated with Lapatinib resistance.
- To explore potential therapeutic targets for overcoming Lapatinib resistance.
Main Methods:
- Utilized bioinformatics strategies on gene expression profiles of Lapatinib-sensitive and resistant breast cancer cell lines (SKBR3 and SKBR3-R).
- Identified DEGs using dChip software.
- Performed gene ontology (GO) and pathway enrichment analyses (DAVID database).
- Constructed and analyzed protein-protein interaction (PPI) networks (STRING database).
Main Results:
- Identified 300 DEGs, including HSPA5, MAP1LC3A, and RASSF2.
- GO analysis revealed associations with cell membrane, stimulus, and binding.
- KEGG pathway analysis highlighted enriched pathways: PPAR signaling, cytokine-cytokine receptor interaction, and pathways in cancer.
- PPI network analysis identified hub genes like PPARG, TGFBI, and JUN potentially linked to Lapatinib resistance.
Conclusions:
- This study provides novel insights into the molecular basis of Lapatinib resistance in breast cancer.
- Identified several significant hub genes (e.g., PPARG, TGFBI, JUN) as potential therapeutic targets.
- Findings pave the way for developing strategies to combat Lapatinib-resistant breast cancer.