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Updated: Jul 31, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Genomic Index of Sensitivity to Chemotherapy for Triple Negative Breast Cancer
Ahammad Sameer C1, Manan Shah2, Dipayan Nandy2
1Department of Applied Sciences, Parul University, Vadodara, India.
Objective:
Patients with triple-negative breast cancer (TNBC) frequently develop resistance to chemotherapy. Studies have shown that microRNAs (miRNAs) are often aberrantly expressed in TNBC and are associated with drug resistance. However, a prognostic strategy that correlates miRNAs with chemotherapy resistance remains largely unknown.
Methods:
To identify breast cancer chemoresistance-associated miRNAs, the miRNA microarray dataset GSE71142 was downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) in chemoresistant groups were identified using the LIMMA package in R. Potential target genes were predicted using the miRTarBase 9. Functional and pathway enrichment analyses was done using WebGestalt. A protein-protein interaction network was visualized using Cytoscape software. The top six hub genes regulated by DE-miRNAs were identified using the random forest model. The chemotherapy resistance index (CRI) in TNBC was defined as sum of the median expression levels of the top six hub genes. The association of CRI with distant relapse risk was evaluated using point-biserial correlation coefficient in the validation cohorts of patients with TNBC. The correlation between CRI and cumulative hazard rate was estimated using the Cox model, and the predicted rate of distant relapse was obtained from the Breslow-type estimator of the survival function. All statistical computations were performed using Origin2019b.
Results:
A total of 12 DE-miRNAs were screened, including six upregulated and six downregulated miRNAs in chemoresistant breast cancer tissues compared with chemosensitive tissues. Based on fold changes, miR-214-3p, miR-4758-3p, miR-200c-3p, miR-4254, miR-140-3p, and miR-24-3p were the top six most upregulated miRNAs, whereas miR-142-5p, miR-146-5p, miR-1268b, miR-1275, miR-4447, and miR-4472 were the top six most downregulated miRNAs. The top three hub genes for upregulated miRNAs were RAC1, MYC, and CCND1 and for downregulated miRNAs were IL-6, SOCS1, and PDGFRA. CRI was significantly associated with the risk of distant relapse.
Conclusion:
CRI predicted survival benefits with reduced hazard rate.
Insights
This study identifies microRNAs (miRNAs) associated with chemotherapy resistance in triple-negative breast cancer (TNBC). A novel Chemoresistance Index (CRI) based on miRNA-regulated hub genes predicts distant relapse risk and survival benefits in TNBC patients.
Area of Science:
- Oncology
- Genetics
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) frequently exhibits chemotherapy resistance.
- Aberrant microRNA (miRNA) expression is linked to drug resistance in TNBC.
- A prognostic strategy correlating miRNAs with chemotherapy resistance is needed.
Purpose of the Study:
- To identify breast cancer chemoresistance-associated miRNAs.
- To develop a prognostic index based on miRNA-regulated genes.
- To evaluate the index's association with distant relapse risk in TNBC.
Main Methods:
- Downloaded miRNA microarray dataset GSE71142.
- Identified differentially expressed miRNAs (DE-miRNAs) using LIMMA.
- Predicted target genes and performed functional enrichment analysis.
- Constructed protein-protein interaction network and identified hub genes.
- Defined Chemoresistance Index (CRI) based on top six hub genes.
- Evaluated CRI association with distant relapse risk using correlation and Cox models.
Main Results:
- Screened 12 DE-miRNAs (six upregulated, six downregulated).
- Identified top upregulated miRNAs (e.g., miR-214-3p) and downregulated miRNAs (e.g., miR-142-5p).
- Determined top hub genes for upregulated (RAC1, MYC, CCND1) and downregulated (IL-6, SOCS1, PDGFRA) miRNAs.
- Found significant association between CRI and distant relapse risk.
Conclusions:
- The developed Chemoresistance Index (CRI) is significantly associated with distant relapse risk in TNBC.
- CRI predicts survival benefits, indicating a reduced hazard rate for patients.
- This miRNA-based index offers a potential prognostic strategy for TNBC management.
