Multidisciplinary Cancer Investigation
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Multidisciplinary Cancer Investigation
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1- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran ,dr.reza.mahdian@gmail.com
2- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran ,
Abstract: (4 Views)
Introduction: Understanding the molecular mechanisms underlying resistance to CDK4/6 inhibitors in breast cancer is crucial. As these drugs target key regulators of the cell cycle and proliferation, genes involved in the cyclin–CDK–RB–E2F signaling pathway are strong candidates for mediating or predicting therapeutic resistance.
Materials and Methods: RNA-Seq data (GSE130437) from MCF7 (HR+/HER2−) and MDA-MB231 (triple-negative) breast cancer cell lines, before and after induction of palbociclib resistance, were analyzed. Gene expression of CDK4, CDK6, CCND1, RB1, E2F1–3, FOXM1, and PLK1 was evaluated using two-way ANOVA and Pearson correlation to identify transcriptional alterations associated with acquired resistance. FPKM values were used to assess differences in expression.
Results: Gene expression profiling in MCF7 (HR+/HER2−) and MDA-MB231 (triple-negative) breast cancer cell lines before and after developing resistance to palbociclib revealed distinct molecular patterns. In MCF7, resistance was associated with a general downregulation of cell cycle regulators, including RB1, FOXM1, PLK1, E2F1, E2F2, and the cyclin D–CDK4/6 complex, with CCND1 showing a significant decrease. In contrast, MDA-MB231 displayed a strong upregulation of CCND1 (p < 0.000001) upon resistance, while other genes showed minimal or non-significant changes. Correlation analyses highlighted CCND1, CDK4, and PLK1 as key expression hubs, suggesting subtype-specific transcriptional adaptations to CDK4/6 inhibition.
Conclusions: Resistance to CDK4/6 inhibitors in breast cancer involves distinct, subtype-specific transcriptional changes. MCF7 cells show downregulation of cell-cycle and cyclin D–CDK4/6 pathway genes, whereas MDA-MB231 cells exhibit marked upregulation of CCND1, indicating that CCND1 and related regulators are potential biomarkers and therapeutic targets for overcoming resistance.
Materials and Methods: RNA-Seq data (GSE130437) from MCF7 (HR+/HER2−) and MDA-MB231 (triple-negative) breast cancer cell lines, before and after induction of palbociclib resistance, were analyzed. Gene expression of CDK4, CDK6, CCND1, RB1, E2F1–3, FOXM1, and PLK1 was evaluated using two-way ANOVA and Pearson correlation to identify transcriptional alterations associated with acquired resistance. FPKM values were used to assess differences in expression.
Results: Gene expression profiling in MCF7 (HR+/HER2−) and MDA-MB231 (triple-negative) breast cancer cell lines before and after developing resistance to palbociclib revealed distinct molecular patterns. In MCF7, resistance was associated with a general downregulation of cell cycle regulators, including RB1, FOXM1, PLK1, E2F1, E2F2, and the cyclin D–CDK4/6 complex, with CCND1 showing a significant decrease. In contrast, MDA-MB231 displayed a strong upregulation of CCND1 (p < 0.000001) upon resistance, while other genes showed minimal or non-significant changes. Correlation analyses highlighted CCND1, CDK4, and PLK1 as key expression hubs, suggesting subtype-specific transcriptional adaptations to CDK4/6 inhibition.
Conclusions: Resistance to CDK4/6 inhibitors in breast cancer involves distinct, subtype-specific transcriptional changes. MCF7 cells show downregulation of cell-cycle and cyclin D–CDK4/6 pathway genes, whereas MDA-MB231 cells exhibit marked upregulation of CCND1, indicating that CCND1 and related regulators are potential biomarkers and therapeutic targets for overcoming resistance.
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Subject:
Diagnosis and Staging
Received: 2025/11/17 | Accepted: 2026/07/15
Received: 2025/11/17 | Accepted: 2026/07/15
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