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Doxorubicin downregulates cell cycle regulatory hub genes in breast cancer cells
Mano Chitra Karthikeyan1, Chandhru Srinivasan1, Kowsika Prabhakar1
1Molecular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620 024, India.
Abstract:
Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.
Insights
This study identified nine key genes crucial for breast cancer (BC) progression. Doxorubicin (DOX) treatment effectively reduced the expression of these genes, reinforcing DOX
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Breast cancer (BC) is a leading global cancer with complex developmental mechanisms.
- Identifying key genes is crucial for advancing BC therapeutics.
- Doxorubicin (DOX) is a common chemotherapy agent for BC.
Purpose of the Study:
- To investigate the influence of doxorubicin (DOX) on key genes in breast cancer (BC).
- To identify novel therapeutic targets for BC treatment through bioinformatic analysis.
Main Methods:
- Meta-analysis of publicly available breast cancer gene expression datasets from the Gene Expression Omnibus (GEO).
- Identification of common differentially expressed genes (DEGs) using GEO2R.
- Bioinformatic analysis including KEGG pathway enrichment, Cytoscape for hub gene identification, and validation using GEPIA and UALCAN databases.
- Quantitative real-time PCR (qRT-PCR) to confirm gene expression changes in BC cell lines post-DOX treatment.
Main Results:
- A total of 23 common DEGs were identified, with nine upregulated genes identified as potential hub genes (NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1).
- These hub genes were significantly enriched in the cell cycle pathway and were associated with unfavorable overall survival in BC patients across all subclasses.
- qRT-PCR confirmed that DOX treatment significantly reduced the expression of these nine hub genes in BC cell lines.
Conclusions:
- The identified hub genes play a critical role in breast cancer progression and are targeted by doxorubicin.
- Doxorubicin remains an effective therapeutic option for breast cancer.
- Developing modified doxorubicin formulations could potentially reduce toxicity and overcome resistance, enhancing its efficacy.
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