The Impact of Olaparib on Metabolic Pathways in Triple Negative Breast Cancer: A Bioinformatics Approach

Year 2024, Volume: 6 Issue: 3, 555 - 560, 24.09.2024

Yalda Hekmatshoar

https://doi.org/10.37990/medr.1529503

Abstract

Aim: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer (BC) characterized by the lacking estrogen receptors, progesterone receptors, and HER2 expression, making it challenging to treat with targeted therapies. Olaparib, a PARP inhibitor, has shown promise in treating TNBC, particularly in patients with BRCA1 or BRCA2 mutations. This study aims to elucidate the metabolic pathways affected by olaparib in TNBC using bioinformatics analysis.
Material and Method: For bioinformatics analysis, mRNA microarray data of control MDA-MB-468 cells (non-treated) and OlaR MDA-MB-468 (3μM olaparib-treated MDA-MB-468 cells) with the study numbered GSE165914 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to analyze and identify differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto gene and genome encyclopedia (KEGG) analysis were carried out for DEGs to determine significant genes and the biological pathways influenced by olaparib treatment. Protein-protein interaction (PPI) network analysis further identified key proteins and interactions within these pathways.
Results: For GEO2R analysis adjusted P-value<0.05 and |log2FC|>1.0 were selected. The results revealed the upregulation of 2277 genes and downregulation of 2298 genes in olaparib-treated cells compared to the controls. It was reported that DEGs enriched in pathways including, metabolic pathways, pathways in cancer, chemical carcinogenesis - reactive oxygen species, cell cycle, autophagy - animal, Efferocytosis and TNF signaling pathway. Both upregulated and downregulated DEGs were associated with metabolic pathways. Moreover, NDUFA5, NDUFA6, NDUFS6, NDUFB3, NDUFB10, NDUFB7, NDUFA7, NDUFA9, H2AC8, H2AC13, H2AC17, H4C11, H4C12, H2BC12, H2BC21 and H2BC4 were identified as the most significant candidate genes.
Conclusion: This comprehensive bioinformatics approach provides insights into the molecular mechanisms of olaparib's action and identifies potential targets for combination therapies to enhance treatment efficacy in breast cancer.

Keywords

Triple-negative breast cancer, olaparib, bioinformatics, gene expression omnibus, gene expression

Ethical Statement

N/A

Supporting Institution

N/A

Thanks

N/A

References

• Qu F, Wang G, Wen P, et al. Knowledge mapping of immunotherapy for breast cancer: a bibliometric analysis from 2013 to 2022. Hum Vaccin Immunother. 2024;20:2335728.
• Barzaman K, Karami J, Zarei Z, et al. Breast cancer: biology, biomarkers, and treatments. Int Immunopharmacol. 2020;84:106535.
• Chang-Qing Y, Jie L, Shi-Qi Z, et al. Recent treatment progress of triple negative breast cancer. Prog Biophys Mol Biol. 2020;151:40-53.
• Zhang ZJ, Liao YT, Wang W, et al. Discovery of acetophenone/piperazin-2-one hybrids as selective anti-TNBC cancer agents by causing DNA damage. Bioorg Med Chem Lett. 2024;108:129802.
• Han Y, Yu X, Li S, et al. New perspectives for resistance to parp inhibitors in triple-negative breast cancer. Front Oncol. 2020;10:578095.
• Gajan A, Sarma A, Kim S, et al. Analysis of adaptive olaparib resistance effects on cisplatin sensitivity in triple negative breast cancer cells. Front Oncol. 2021;11:694793.
• Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. Target Oncol. 2021;16:255-82.
• Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72:5588-99.
• Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-33.
• Bhamidipati D, Haro-Silerio JI, Yap TA, Ngoi N. PARP inhibitors: enhancing efficacy through rational combinations. Br J Cancer. 2023;129:904-16.
• Sinha S, Chatterjee S, Paul S, et al. Olaparib enhances the Resveratrol-mediated apoptosis in breast cancer cells by inhibiting the homologous recombination repair pathway. Exp Cell Res. 2022;420:113338.
• Lee JM, Cimino-Mathews A, Peer CJ, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-Ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women's cancers: a dose-escalation, phase I study. J Clin Oncol. 2017;35:2193-202.
• Hekmatshoar Y, Rahbar Saadat Y, Ozkan T, et al. Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a bioinformatics study. Nucleosides Nucleotides Nucleic Acids. 2024;43:664-84.
• Karadag Gurel A, Gurel S. To detect potential pathways and target genes in infantile Pompe patients using computational analysis. Bioimpacts. 2022;12:89-105.
• Jiang B, Wu S, Zeng L, et al. Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression. Cancer Cell Int. 2024;24:99.
• Sridharan S, Howard CM, Tilley AMC, et al. Novel and alternative targets against breast cancer stemness to combat chemoresistance. Front Oncol. 2019;9:1003.
• James N, Owusu E, Rivera G, Bandyopadhyay D. Small molecule therapeutics in the pipeline targeting for triple-negative breast cancer: origin, challenges, opportunities, and mechanisms of action. Int J Mol Sci. 2024;25:6285.
• Liao M, Zhang J, Wang G, et al. Small-molecule drug discovery in triple negative breast cancer: current situation and future directions. J Med Chem. 2021;64:2382-418.
• Huang YP, Chang NW. PPARalpha modulates gene expression profiles of mitochondrial energy metabolism in oral tumorigenesis. Biomedicine (Taipei). 2016;6:3.
• Shimada T, Moriuchi R, Mori T, et al. Identification of NADH dehydrogenase 1 alpha subcomplex 5 capable to transform murine fibroblasts and overexpressed in human cervical carcinoma cell lines. Biochem Biophys Res Commun. 2006;339:852-7.
• Lu H, Zhu Q. Identification of key biological processes, pathways, networks, and genes with potential prognostic values in hepatocellular carcinoma using a bioinformatics approach. Cancer Biother Radiopharm. 2021;36:837-49.
• McKenzie M, Tucker EJ, Compton AG, et al. Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. J Mol Biol. 2011;414:413-26.
• Zhao J, Wang X, Zhu H, et al. Integrative analysis of bulk RNA-Seq and single-cell RNA-Seq unveils novel prognostic biomarkers in multiple myeloma. Biomolecules. 2022;12:1855.
• Chung IC, Chen LC, Tsang NM, et al. Mitochondrial oxidative phosphorylation complex regulates NLRP3 inflammasome activation and predicts patient survival in nasopharyngeal carcinoma. Mol Cell Proteomics. 2020;19:142-54.